WO2012030647A1 - Treatment of cystic fibrosis using calcium lactate, leucine and sodium chloride in a respiraple dry powder - Google Patents
Treatment of cystic fibrosis using calcium lactate, leucine and sodium chloride in a respiraple dry powder Download PDFInfo
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- WO2012030647A1 WO2012030647A1 PCT/US2011/049342 US2011049342W WO2012030647A1 WO 2012030647 A1 WO2012030647 A1 WO 2012030647A1 US 2011049342 W US2011049342 W US 2011049342W WO 2012030647 A1 WO2012030647 A1 WO 2012030647A1
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- dry powder
- formulation
- calcium
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- dose
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Definitions
- Cystic fibrosis is an inherited chronic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
- the mutations result in advanced or abolished CFTR activity and dysregulated ion transport across the epithelial membrane of airway epithelial cells.
- This defect causes the body to produce unusually thick, sticky mucus, that is not cleared well by mucociliary clearance and clogs the lungs, leading to lung infections, in particular recurrent pneumonia.
- Pseudomonas aeruginosa is a common bacterium that colonizes the airway and is associated with a decline in lung function and ultimately respiratory failure.
- Pseudomonas aeruginosa employs intricate regulatory signaling pathways to convert from the planktonic to biofilm state and to mature the structure of the biofilm. It is the formation and maintenance of the biofilm that is credited with the ability of Pseudomonas aeruginosa to persist in the airway following colonization.
- Treatment of CF involves the use of antibiotics to treat and prevent lung infections, the use of recombinant human DNAse to reduce the viscosity of the airway lining fluid by breaking down DNA contained therein, and in some cases lung transplantation.
- Another therapy for CF involves the administration of aerosolized hypertonic saline solutions to the lungs.
- Hypertonic saline therapy is reported to improve mucociliary clearance and to reduce the number of exacerbations experienced by patients, resulting in improvements in lung function, less antibiotic being used to treat exacerbations, and a decrease in the number of days that patients are unable to work.
- Hypertonic saline is thought to produce these benefits by improving the hydration of the airway lining fluid by the delivery of water to the lungs and by osmotic effects, which increases the volume of liquid at the airway surface and results in improved mucociliary clearance.
- the invention relates to a method for treating cystic fibrosis, comprising administering to an individual with cystic fibrosis an effective amount of a calcium salt formulation.
- the calcium salt formulation is a respirable dry powder containing respirable dry particles that comprise, on a dry basis, about 20% (w/w) leucine, about 75% (w/w) calcium lactate, and about 5%> (w/w) sodium chloride; or about 37.5%> (w/w) leucine, about 58.6%) (w/w) calcium lactate, and about 3.9%> (w/w) sodium chloride.
- Other preferred dry powder for use in treating CF include dry powders containing respirable dry particles that comprise, on dry basis:
- the respirable dry particles have a volume median geometric diameter (VMGD) of 5 microns or less as measured at the one bar dispersion setting on ae HELOS/RODOS laser diffraction system.
- the respirable dry particles have a volume median geometric diameter (VMGD) of less than 5 microns, such as between 1 and 3 microns, as measured at the one bar dispersion setting on a HELOS/RODOS laser diffraction system.
- the respirable dry powders have a Hausner Ratio of at least 1.5, preferably at least 2.0. In some embodiments, the dry powders have a Hausner Ratio of at least 1.4.
- the respirable dry powders have a dispersibility ratio at 1 bar/4 bar of less than 1.5, such as between 1.0 and 1.2, as measured at the 1 bar and 4 bar dispersion settings on the
- the respirable dry powders have a dispersibility ratio at 0.5 bar/4 bar of less than 1.5, such as between 1.0 and 1.3, as measured by laser diffraction (HELOS/RODOS system).
- the respirable dry powders have a Fine Particle Fraction (FPF) of less than 3.4 microns of at least 20% or at least 30%.
- the respirable dry powders have a Fine Particle Fraction (FPF) of less than 5.6 microns of at least 30%, or at least 40%, or at least 50%.
- the respirable dry powders are characterized by a high emitted dose.
- a Capsule Emitted Powder Mass (CEPM) of at least about 80%> of said respirable dry powder contained in a unit dose container that contains 50 mg of said dry powder, in a dry powder inhaler is achieved when a total inhalation energy of less than about 1 Joule is applied to said dry powder inhaler.
- a Capsule Emitted Powder Mass (CEPM) of at least about 80% of said respirable dry powder contained in a unit dose container that contains 40 mg of said dry powder, in a dry powder inhaler is achieved when a total inhalation energy of less than about 1 Joule is applied to said dry powder inhaler.
- the respirable dry powders can contain amorphous and/or crystalline states.
- calcium lactate can be amorphous and the sodium chloride and/or leucine can be crystalline, or calcium lactate and leucine can be amorphous.
- the calcium lactate and sodium chloride are substantially in the amorphous phase and the leucine is in either the crystalline and/or amorphous phase.
- the respirable dry powders can further comprise an additional therapeutic agent.
- the invention also relates to a method of reducing the formation of a bio film in a cystic fibrosis patient comprising administering to an individual with cystic fibrosis an effective amount of a calcium salt formulation (e.g., a dry powder described herein).
- a calcium salt formulation e.g., a dry powder described herein.
- the invention also relates to a method of disrupting or dispersing a bio film in a cystic fibrosis patient comprising administering to an individual with cystic fibrosis an effective amount of a calcium salt formulation (e.g., a dry powder described herein).
- a calcium salt formulation e.g., a dry powder described herein.
- the invention also relates to a method for treating or preventing an acute exacerbation of cystic fibrosis comprising administering to the respiratory tract of a patient in need thereof an effective amount of calcium salt formulation (e.g., a dry powder described herein).
- an effective amount of calcium salt formulation e.g., a dry powder described herein.
- FIG. 1 A is a schematic showing an in vitro simulated cough system.
- Bottled compressed air, filtered to remove particles >0.01 micrometers in diameter is used to fill the Pressurized Chamber to a set pressure to mimic the flow of a cough maneuver.
- the solenoid valve is actuated, releasing the compressed air through a pneumotachometer, which records the air flow rate, and a low resistance HEPA filter. Air enters the trough with airflow passing over the mucus mimetic and generating aerosol particles.
- the drip trap prevents any bulk motion of the mucus mimetic from entering the holding chamber while the generated aerosol enters the expandable holding chamber.
- the optical particle counter sizes and counts the aerosol particles in the holding chamber as it draws the air out of the chamber.
- FIG. IB is a graph showing calcium chloride is more effective than 0.90% saline in the suppression of bioparticle formation in an in vitro model.
- FIG. 1C is a graph showing suppresssion of pathogen containing bioparticle formation by exposure to 1.29% calcium chloride (0.12M) in 0.90% sodium chloride solution.
- Mucus mimetics were mixed with K. pneumoniae and added to the cough system. Following simulated cough, bioparticles were collected in liquid broth and the number of CFU determined. Mimetic treated with calcium aerosols reduced the number of particles containing K. pneumoniae by 75% relative to the untreated control.
- FIG. 2 A is a graph showing that mice infected with S. pneumoniae and treated two hours after infection with CaCl 2 -saline aerosol (1.29% calcium chloride (0.12M) in 0.90% sodium chloride) for fifteen minutes, have less bacterial burden than untreated controls.
- Each data point represents the data obtained from a single animal.
- the bar for each group represents the geometric mean of the group.
- FIG. 2B is a graph showing that mice treated with CaCb-saline aerosol (1.29% calcium chloride (0.12M) in 0.90% sodium chloride) for fifteen minutes, two hours before infection with S. pneumoniae, have less bacterial burden than untreated controls.
- Each data point represents the data obtained from a single animal.
- the bar for each group represents the geometric mean of the group.
- FIG. 3B is a graph showing that mice infected with S. pneumoniae and pretreated with saline aerosol (0.90% sodium chloride) for fifteen minutes two hours before infection have a higher bacterial burden than animals pretreated with CaCb-saline aerosol (1.29% calcium chloride (0.12M) in 0.9% sodium chloride). Pooled data from multiple experiments are shown. Each data point represents the data obtained from a single animal. The bar for each group represents the geometric mean of the group. The data were statistically analyzed using a Mann- Whitney U test.
- FIG. 4 A shows that formulations comprising calcium chloride and sodium chloride (Ca 2+ :Na + at 8: 1 molar ratio) reduced lung bacterial burden.
- Mice were treated with the indicated formulations using a PariLC Sprint nebulizer and subsequently infected with S. pneumoniae. The lung bacterial burden in each animal is shown.
- Each circle represents data from a single animal and the bar depicts the geometric mean with a 95% confidence interval.
- Data for the NaCl, 0.5X and IX groups are pooled from two or three independent experiments. Data from the 2X and 4X groups are from a single experiment.
- FIG. 4B shows that increasing calcium dose with longer nebulization times did not significantly impact therapeutic efficacy.
- the lung bacterial burden in each animal is shown.
- Each circle represents data from a single animal and the bar depicts the geometric mean. Dosing times of 3 minutes or greater significantly reduced bacterial burdens relative to controls (one-way ANOVA; Tukey's multiple comparison post- test).
- FIG. 4C is a graph showing the inhibition of bacterial infection by ampicillin, Formulation 10 (IX), saline, and Formulation 10 plus Ampicillin (Ampicillin+lX).
- FIG. 5A, FIG. 5B, and FIG 5C are graphs showing that a significant reduction in macrophage, neutrophil, and lymphocyte inflammation, as represented by cell counts, was seen when Tobacco Smoked Mice were treated q.d. with either prophylactic dosing or therapeutic dosing with Formulation 29, and with a positive control.
- FIG. 6A and FIG. 6B are graphs showing that a significant reduction in KC and MIP2, two key neutrophil chemokines, was seen when TS Mice were treated q.d. with Formulations 30- A and IV-A.
- FIG. 7 is a graph showing that a significant increase in mucociliary clearance was seen when sheep were treated with Formulations 29 and 13-A.
- FIG. 8 is a graph showing a decrease in airway resistance was observed when mice were treated with Formulation XI and 14-A and then challenged with methacholine chloride (MCh) as compared to when the sham (Placebo-B) treatment group was challenged with MCh.
- MCh methacholine chloride
- FIG. 9 is a graph showing a decrease in airway resistance was observed when mice were treated with Formulation XIV and 14-B and then challenged with methacholine chloride (MCh) as compared to when the sham (Placebo-B) treatment group was challenged with MCh.
- MCh methacholine chloride
- the invention relates to methods for the treatment of CF and provides several advantages over prior approaches.
- IX tonicity refers to a solution that is isotonic relative to normal human blood and cells. Solutions that are hypertonic in comparison to normal human blood and cells are described relative to a IX solution using an appropriate multiplier.
- a hypertonic solution may have 1.1X, 1.5X, 2X, 3X, 4X, 5X, 6X, 7X, 8X, 9X, 10X, 1 IX or greater tonicity.
- aerosol refers to any preparation of a fine mist of particles (including liquid and non-liquid particles, e.g., dry powders), typically with a volume median geometric diameter of about 0.1 to about 30 microns or a mass median aerodynamic diameter of between about 0.5 and about 10 microns.
- volume median geometric diameter for the aerosol particles is less than about 10 microns.
- the preferred volume median geometric diameter for aerosol particles is about 5 microns.
- the aerosol can contain particles that have a volume median geometric diameter between about 0.1 and about 30 microns, between about 0.5 and about 20 microns, between about 0.5 and about 10 microns, between about 1.0 and about 3.0 microns, between about 1.0 and 5.0 microns, between about 1.0 and 10.0 microns, between about 5.0 and 15.0 microns.
- the mass median aerodynamic diameter is between about 0.5 and about 10 microns, between about 1.0 and about 3.0 microns, or between about 1.0 and 5.0 microns.
- dry powder refers to a composition that contains finely dispersed respirable dry particles that are capable of being dispersed in an inhalation device and subsequently inhaled by a subject.
- Such a dry powder or dry particle may contain up to about 25%, up to about 20%, or up to about 15 > water or other solvent, or be substantially free of water or other solvent, or be anhydrous.
- the invention provides methods for the treatment of CF.
- treatment is not necessarily curative, but is aimed at maintenance therapy or alleviating symptoms and/or discomfort.
- the method can be used as stand alone or front line therapy or incorporated into a larger therapeutic regimen.
- the method comprises administering to an individual with CF an effective amount of a hypertonic calcium salt formulation as described herein.
- the hypertonic calcium salt formulation is administered to the respiratory tract as an aerosol, preferably by inhalation.
- hypertonic calcium salt formulation can be administered as a dry powder.
- hypertonic calcium salt formulation includes hypertonic liquid formulations, and also includes dry powders that contain calcium in an amount that improves lung mucus hydration, which is preferably determined or assessed by an increased rate of mucociliary clearance (Groth et al, Thorax, 43(5):360-365 (1988)).
- the method provides several advantages. Without wishing to be bound by any particular theory, it is believed that the hypertonic calcium salt formulations will increase the volume of liquid on the airway surface through osmotic effects and that this hydrating effect will be more persistent than the hydration achieved using hypertonic saline.
- calcium inhibits the ability of certain pathogens to cross mucus layers and inhibits viral infectivity and replication.
- Hypertonic calcium and dry powder salt formulations can prevent and treat bacterial infection. Accordingly, these activities of calcium provide an added benefit of reducing exacerbations caused by lung infections.
- Calcium salt formulations such as hypertonic calcium and dry powder salt formulations, can inhibit or prevent the formation of bio films, and can disrupt and/or disperse pre-existing biofilms.
- the invention provides methods to delay, reduce or prevent infection and pathogen colonization of the lungs of an individual with CF.
- the method comprises administering to an individual with CF an effective amount of a calcium salt formulation, such as a hypertonic calcium salt formulation as described herein,
- the calcium salt formulation is administered to the respiratory tract as an aerosol, preferably by inhalation.
- the invention relates to a method of reducing or preventing the formation of a biofilm in a CF patient comprising administering to an individual with CF an effective amount of a calcium salt formulation, wherein the calcium salt formulation is administered as an aerosol to the respiratory tract of said individual.
- the invention also relates to a method of disrupting or dispersing a biofilm in a CF patient comprising administering to an individual with CF an effective amount of a calcium salt formulation, wherein the calcium salt formulation is administered as an aerosol to the respiratory tract of said individual.
- CF patients may experience exacerbation caused by infections by Streptococcus pneumoniae, Staphylococcus aureus, Staphylococcus spp., Streptococcus spp., Streptococcus agalactiae, Haemophilus influenzae, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Moraxella catarrhalis, Chlamydophila pneumoniae, Mycoplasma pneumoniae, Legionella pneumophila, Enterobacter spp., Acinetobacter spp., Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus, Stenotrophomonas maltophilia, Burkholderia cepatia, influenza virus, respiratory syncytial virus, adenovirus, metapneumovirus, cytomegalovirus, herpes simplex virus and combinations thereof.
- CF patient may also experience
- Mild exacerbations of CF can also be caused by all of the below, namely, by the causes of influenza, influenza-like illness, and community associate pneumonia.
- exacerbations can be caused by opportunitistic bacterial pathogens, such as Pseudomonas aeruginosa, Burkholderia cepacia, Burkholderia pseudomallei, and the like, that characterize CF airway colonization, and also by atypical mycobacteria and Stenotrophomonas.
- influenza is caused by either the influenza A or the influenza B virus.
- an influenza-like illness is caused by RSV, rhinovirus, adenovirus, parainfluenza, human coronaviruses (including the virus that causes severe acute respiratory syndrome) and metapneumovirus.
- community associated pneumonia is caused by at least one of the following bacteria: Moraxella catarralis, Mycoplasma pneumoniae,
- CAP may also be caused by at least one of the following fungi: Coccidiomycosis, histoplasmosis, and cryptococcocus.
- CAP can be caused by Gram-positive or Gram-negative bacteria associated with causing pneumonia.
- the invention relates to a method for treating or preventing an acute exacerbation of CF comprising administering to the respiratory tract of a patient in need thereof an effective amount of calcium salt formulation.
- Another advantage provided by the method of the invention is a reduction in contagion.
- Specific concerns over patient-to-patient spread of infectious agents including Burkholderia cepatia in the CF clinic have been a concern of care providers in recent years.
- Administration of calcium salts in accordance with the method of the invention decreases the amount of particles that are exhaled by an individual with CF. This reduces the spread of pathogens that are present in the exhaled particles. Accordingly, the spread of lung infection from an individual with CF to others ⁇ e.g. care providers, family members, other individuals with CF) is reduced.
- the hypertonic calcium salt formulations or calcium salt formulations are administered to the respiratory tract, and can be administered in any suitable form, such as a solution, a suspension, an emulsion, a spray, a mist, a foam, a gel, a vapor, droplets, particles, or a dry powder.
- the hypertonic calcium formulation or calcium salt formulation is aerosolized for administration to the respiratory tract.
- formulations or calcium salt formulations can be aerosolized for administration via the oral airways using any suitable method and/or device, and many suitable methods and devices are conventional and well-known in the art.
- hypertonic calcium salt formulations or calcium salt formulations can be aerosolized using a nebulizer, an atomizer, a continuous sprayer, an oral spray, a metered dose inhaler ⁇ e.g., a pressurized metered dose inhaler (pMDI) including HFA propellant, or a non-HFA propellant) with or without a spacer or holding chamber, or a dry powder inhaler (DPI).
- pMDI pressurized metered dose inhaler
- DPI dry powder inhaler
- Hypertonic calcium salt formulations or calcium salt formulations can be aerosolized for administration via the nasal airways using a nasal pump or sprayer, a metered dose inhaler (e.g., a pressurized metered dose inhaler (pMDI) including HFA propellant, or a non-HFA propellant) with or without a spacer or holding chamber, a nebulizer with or without a nasal adapter or prongs, an atomizer, a continuous sprayer, or a DPI.
- a metered dose inhaler e.g., a pressurized metered dose inhaler (pMDI) including HFA propellant, or a non-HFA propellant
- pMDI pressurized metered dose inhaler
- pMDI pressurized metered dose inhaler
- pMDI pressurized metered dose inhaler
- pMDI pressurized metered dose inhaler
- pMDI pressurized metered dose inhaler
- the geometry of the airways is an important consideration when selecting a suitable method for producing and delivering aerosols to the lungs.
- the lungs are designed to entrap particles of foreign matter that are breathed in, such as dust.
- Impaction in the upper airways occurs when particles are unable to stay within the air stream, particularly at airway branches. Impacted particles are adsorbed onto the mucus layer covering bronchial walls and eventually cleared from the lungs by mucociliary action. Impaction mostly occurs with particles over 5 ⁇ in aerodynamic diameter. Smaller particles (those less than about 3 ⁇ in aerodynamic diameter) tend to stay within the air stream and to be advected deep into the lungs.
- a suitable method e.g., nebulization, dry powder inhaler
- the desired region of the respiratory tract such as the deep lung (generally particles between about 0.6 microns and 3 microns in diameter), the upper airway (generally particles of about 3 microns or larger diameter), or the deep lung and the upper airway.
- the deep lung generally particles between about 0.6 microns and 3 microns in diameter
- the upper airway generally particles of about 3 microns or larger diameter
- particles with an aerodynamic diameter of about 1 micron to about 3 microns can be delivered to the deep lung. Larger aerodynamic diameters, for example, from about 3 microns to about 5 microns can be delivered to the central and upper airways.
- a dry powder formulation is administered to the small airways.
- the dry powder preferably contains respirable particles that have a VMDG and/or MMAD that is suitable for delivery to the small airways, such as a VMGD and/or MMAD of about 0.5 ⁇ to about 3 ⁇ , about 0.75 ⁇ to about 2 ⁇ , or about 1 ⁇ ⁇ about 1.5 ⁇ .
- An "effective amount" of hypertonic calcium salt formulation or calcium salt formulation is administered to an individual with CF.
- An effective amount is an amount that is sufficient to achieve the desired therapeutic or prophylactic effect under the conditions of administration, such as an amount sufficient to increase the rate of mucociliary clearance, to reduce pathogens in an individual, to inhibit pathogens passing through the lung mucus or airway lining fluid, to decrease the incidence or rate of infection with pathogens that cause pneumonia, and/or to decrease the shedding of exhaled particles containing pathogens that cause pneumonia.
- an amount effective to reduce or prevent bacterial biofilm formation, or to disrupt and/or disperse pre-existing biofilms is administered.
- the dose that is administered is related to the composition of the hypertonic calcium salt formulation or calcium salt formulation (e.g., calcium salt concentration), the rate and efficiency of aerosolization (e.g., nebulization rate and efficiency), and the time of exposure (e.g., nebulization time).
- the composition of the hypertonic calcium salt formulation or calcium salt formulation e.g., calcium salt concentration
- the rate and efficiency of aerosolization e.g., nebulization rate and efficiency
- the time of exposure e.g., nebulization time
- substantially equivalent doses can be administered using a concentrated liquid calcium salt formulation and a short (e.g., 5 minutes) nebulization time, or using a dilute liquid calcium salt formulation and a long (e.g., 30 minutes or more) nebulization time, or using a dry powder formulation and a dry powder inhaler.
- the clinician of ordinary skill can determine appropriate dosages based on these considerations and other factors, for example, the individual's age, sensitivity, tolerance and overall well-being.
- the hypertonic calcium salt formulations or calcium salt formulations can be administered in a single dose or multiple doses as indicated. In some aspects, the hypertonic calcium salt formulation or calcium salt formulations are administered two, three or four times per day.
- an effective amount of a hypertonic calcium salt formulation or calcium salt formulation will deliver a dose of about 0.001 mg Ca +2 /kg body weight/dose to about 2 mg Ca +2 /kg body weight/dose, about 0.002 mg Ca +2 /kg body weight/dose to about 2 mg Ca +2 /kg body weight/dose, about 0.005 mg Ca +2 /kg body weight/dose to about 2 mg Ca +2 /kg body weight/dose, about 0.01 mg Ca +2 /kg body weight/dose to about 2 mg Ca +2 /kg body weight/dose, about 0.01 mg Ca +2 /kg body weight/dose to about 60 mg Ca +2 /kg body weight/dose, about 0.01 mg Ca +2 /kg body weight/dose to about 50 mg Ca +2 /kg body weight/dose, about 0.01 mg Ca +2 /kg body weight/dose to about 40 mg Ca +2 /kg body weight/dose, about 0.01 mg Ca +2 /kg body weight/dose to about 30 mg Ca +
- a hypertonic calcium salt formulation or calcium salt formulation is administered in an amount sufficient to deliver a dose of about 0.1 mg Ca 2+ /kg body weight/dose to about 2 mg Ca 2+ /kg body weight/dose, or about 0.1 mg Ca 2+ /kg body weight/dose to about 1 mg Ca 2+ /kg body weight/dose, or about 0.1 mg Ca 2+ /kg body weight/dose to about 0.5 mg Ca 2+ /kg body weight/dose, or about 0.18 mg Ca 2+ /kg body weight/dose.
- the amount of calcium salt delivered to the respiratory tract is about 0.001 mg/kg body weight to about 60 mg/kg body weight/dose, or about 0.01 mg/kg body weight/dose to about 50 mg/kg body weight/dose, about 0.01 mg/kg body weight/dose to about 40 mg/kg body weight/dose, about 0.01 mg/kg body weight/dose to about 30 mg/kg body weight/dose, about 0.01 mg/kg body weight/dose to about 20 mg/kg body weight/dose, 0.01 mg/kg body weight/dose to about 10 mg/kg body weight/dose, about 0.1 mg/kg body weight/dose to about 10 mg/kg body weight/dose, or about 1 mg/kg body weight/dose to about 10 mg/kg body weight/dose, or about 0.01 mg/kg body weight/dose to about 1 mg/kg body weight/dose, or about 0.1 mg/kg body weight/dose to about 1 mg/kg body weight/dose.
- a hypertonic calcium salt formulation, or calcium salt formulation, that comprises a sodium salt is administered in an amount sufficient to deliver a dose of about 0.001 mg Na + /kg body weight/dose to about 10 mg Na + /kg body weight/dose, or about 0.01 mg Na + /kg body weight/dose to about 10 mg Na + /kg body weight/dose, or about 0.1 mg Na + /kg body weight/dose to about 10 mg Na + /kg body weight/dose, or about 1.0 mg Na + /kg body weight/dose to about 10 mg Na + /kg body weight/dose, or about 0.001 mg Na + /kg body weight/dose to about 1 mg Na + /kg body weight/dose, or about 0.01 mg Na + /kg body weight/dose to about 1 mg Na + /kg body weight/dose, about 0.1 mg Na /kg body weight/dose to about 1 mg Na /kg body weight/dose, about 0.2 mg Na + /kg body
- the amount of sodium salt delivered to the respiratory tract is about 0.001 mg/kg body weight/dose to about 10 mg/kg body weight/dose, or about 0.01 mg/kg body weight/dose to about 10 mg/kg body weight/dose, or about 0.1 mg/kg body weight/dose to about 10 mg/kg body weight/dose, or about 1 mg/kg body weight/dose to about 10 mg/kg body weight/dose, or about 0.001 mg/kg body weight/dose to about 1 mg/kg body weight/dose, or about 0.01 mg/kg body weight/dose to about 1 mg/kg body
- weight/dose or about 0.1 mg/kg body weight/dose to about 1 mg/kg body weight/dose.
- Suitable intervals between doses that provide the desired therapeutic effect can be determined based on the severity of the condition (e.g., infection), the overall well being of the subject and the subject's tolerance to the salt formulations and other considerations.
- a clinician can determine appropriate intervals between doses.
- a salt formulation is administered once, twice, three or four times a day, as needed.
- the hypertonic calcium salt formulation or calcium salt formulation can be administered with one or more other therapeutic agents, such as any one or more of the mucoactive agents, surfactants, cough suppressants, expectorants, steroids, bronchodilators, antihistamines, antibiotics, antiviral agents, or agents that promote airway secretion clearance described herein.
- the other therapeutic agents can be administered by any suitable route, such as orally, parenterally (e.g., intravenous, intra-arterial, intramuscular, or subcutaneous injection), topically, by inhalation (e.g., intrabronchial, intranasal or oral inhalation, intranasal drops), rectally, vaginally, and the like.
- an additional therapeutic agent when administered to a patient with hypertonic calcium salt formulation or calcium salt formulation, they can be administered to provide substantial overlap of pharmacological activity, and the additional therapeutic agent can be administered to the patient before, substantially at the same time, or after the hypertonic calcium salt formulation or calcium salt formulation (e.g., Formulation 29 or 30).
- a LABA such as formoterol
- a short-acting beta agonist such as albuterol
- a dry powder for use in the invention e.g., Formulation 29 or 30
- an additional therapeutic agent can be administered at substantially the same time as two or more separate formulations or as a single formulation (e.g., a blended dry powder, a dry powder formed by co-spray drying the components of Formulation 29 or 30 with an additional therapeutic agent).
- a dry powder of Formulation 29 or 30 can be administered immediately before or immediately after the dosing of Formulation 29 or 30.
- the hypertonic calcium salt formulation or calcium salt formulation (e.g., Formulation 29, Formulation 30, and/or dry powder based on Formulation 29 or 30 that contains an additional therapeutic agent) is administered to a patient who has been pretreated with a bronchodilator, or is administered concurrently with a bronchodilator.
- a bronchodilator it is preferred that the respirable dry powder is administered at a time after the bronchodilator when the onset of bronchodilatory effect is evident or, more preferably, maximal.
- a short acting beta 2 agonist such as albuterol can be administered about 10 minutes to about 30 minutes, preferably, about 15 minutes, prior to administration of the respirable dry powder.
- Pretreatment with a short acting beta 2 agonist such as albuterol is particularly preferred for CF patients.
- Some patients may already be taking bronchodilators, such as LABAs (e.g, fomoterol). Patients who are taking LABAs already receive some degree of bronchorelaxation due to the effects of the LABAs, and therefore further bronchodilation (e.g., using a short acting beta 2 agonist) may not be required or desired.
- LABAs e.g, fomoterol
- hypertonic calcium salt formulation or calcium salt formulation e.g., Formulation 29, Formulation 30, and/or dry powder based on Formulation 29 or 30 that contains an additional therapeutic agent
- LAB A e.g., the respirable dry powder of Formulation XIX
- Hypertonic calcium salt formulations and calcium salt formulations for use in the methods described herein contain a calcium salt (e.g., calcium chloride, calcium lactate, calcium acetate) as an active ingredient, and can optionally contain additional salts or agents.
- a calcium salt e.g., calcium chloride, calcium lactate, calcium acetate
- additional salts or agents e.g., calcium ion, calcium ion, calcium ion, calcium ion (Ca 2+ provide upon dissolution of CaCl 2 ) in the lung mucus or airway lining fluid after administration of the salt formulation.
- Calcium salts provide several advantages, including increasing ciliary beat frequency, drawing water into lungs, persisting longer than sodium, providing an antibacterial effect and modulating the surface
- the hypertonic calcium salt formulation or calcium salt formulation can include any salt form of the elements lithium, sodium, potassium, magnesium, calcium, aluminum, silicon, scandium, titanium, vanadium, chromium, cobalt, nickel, copper, manganese, zinc, tin, silver and similar elements, that is non-toxic when administered to the respiratory tract.
- Additional calcium salts that are suitable for use in the calcium salt formulation include, for example, calcium sulfate, calcium lactate, calcium citrate, calcium carbonate, calcium acetate, calcium phosphate, calcium alginate, calcium stearate, calcium sorbate, calcium gluconate and the like, and combinations thereof.
- Suitable sodium salts include, for example, sodium chloride, sodium acetate, sodium bicarbonate, sodium carbonate, sodium sulfate, sodium stearate, sodium ascorbate, sodium benzoate, sodium biphosphate, sodium phosphate, sodium bisulfite, sodium citrate, sodium lactate, sodium borate, sodium gluconate, sodium metasilicate, and the like, or a combination thereof.
- Suitable magnesium salts include, for example, magnesium carbonate, magnesium sulfate, magnesium stearate, magnesium trisilicate, magnesium chloride, and the like.
- Suitable potassium salts include, for example, potassium bicarbonate, potassium chloride, potassium citrate, potassium borate, potassium bisulfite, potassium biphosphate, potassium alginate, potassium benzoate, and the like.
- Additional suitable salts include cupric sulfate, chromium chloride, stannous chloride, and similar salts.
- Other suitable salts include zinc chloride, aluminum chloride and silver chloride.
- the hypertonic calcium salt formulations or calcium salt formulations can contain about 1.3% to about 13% calcium chloride (w/v).
- the hypertonic calcium salt formulation or calcium salt formulation can contain calcium chloride in an range of 1.3% to about 12.5%, 1.3% to about 12%, 1.3% to about 11.5%, 1.3% to about 11%, 1.3% to about 10.5%, 1.3% to about 10%, 1.3% to about 9.5%, 1.3% to about 9.0%, 1.3% to about 8.5%, 1.3% to about 8%, about 1.3% to about 7.5%, 1.3% to about 7%, 1.3% to about 6.5%, 1.3% to about 6%, 1.3% to about 5.5%, 1.3% to about 5%, about 1.3% to about 4.5%, about 1.3% to about 4%o, about 1.3 %> to about 3.5%>, about 1.3% to about 3%, about 1.3 % to about 2.5%, about 1.3% to about 2%, about 2% to about 13%, about 2.5% to about 13%, about 3% to about 13%), about 3.5% to about 13%
- the hypertonic calcium salts further contain about 0.001% to about 0.9% sodium chloride (w:v).
- the hypertonic calcium salt formulation or calcium salt formulation can contain sodium chloride in a range of about 0.1% to about 0.8%, 0.1% to about 0.7%, 0.1% to about 0.6%, 0.1% to about 0.5%, 0.1% to about 0.4%, 0.1% to about 0.3%, about 0.1% to about 0.2%, about 0.2% to about 0.9%, about 0.3 % to about 0.9%, about 0.4% to about 0.9%, about 0.5 % to about 0.9%, about 0.6% to about 0.9%, about 0.7% to about 0.9%, about 0.8% to about 0.9%, about 0.2% to about 0.8%, about 0.3% to about 0.7%, or about 0.4% to about 0.6% (w:v).
- the hypertonic calcium salt formulation or calcium salt formulation can be a solution, emulsion, or suspension that can be aerosolized, for example using a nebulizer.
- the hypertonic calcium salt formulation or calcium salt formulation is an aqueous solution.
- the hypertonic calcium salt formulation or calcium salt formulation can be dried to form a dry powder, for example by spray drying, cake drying and micronizing, for example, by milling, grinding, or using any other suitable method.
- the hypertonic salt formulations or calcium salt formulations can comprise multiple doses or be a unit dose composition as desired.
- the hypertonic calcium salt formulation or calcium salt formulation is generally prepared in or comprises a physiologically acceptable carrier or excipient.
- suitable carriers include, for example, aqueous, alcoholic/aqueous, and alcohol solutions, emulsions or suspensions, including water, saline, ethanol/water solution, ethanol solution, buffered media, propellants and the like. Any suitable excipient can be included, as desired.
- suitable carriers or excipients include, for example, sugars (e.g., lactose, trehalose), sugar alcohols (e.g., mannitol, xylitol, sorbitol), amino acids (e.g., glycine, alanine, leucine, isoleucine, methionine, tyrosine, tryptophan), dipalmitoylphosphosphatidylcholine (DPPC),
- sugars e.g., lactose, trehalose
- sugar alcohols e.g., mannitol, xylitol, sorbitol
- amino acids e.g., glycine, alanine, leucine, isoleucine, methionine, tyrosine, tryptophan
- DPPC dipalmitoylphosphosphatidylcholine
- DPPG diphosphatidyl glycerol
- DPPS diphosphatidyl glycerol
- DSPC diphosphatidyl glycerol
- DSPE diphosphatidyl glycerol
- POPC l-palmitoyl-2-oleoylphosphatidylcholine
- fatty alcohols polyoxyethylene-9-lauryl ether, surface active fatty, acids, sorbitan trioleate (Span 85), glycocholate, surfactin, poloxomers, sorbitan fatty acid esters, tyloxapol, phospholipids, alkylated sugars, sodium phosphate, maltodextrin, human serum albumin (e.g., recombinant human serum albumin), biodegradable polymers (e.g., PLGA), degradable polymers (e.g., PLGA), degradable polymers (e.g., PLGA), degradable polymers (e.g.,
- Amino acid excipients are preferably racemic, predominately L-isomer, or predominately D- isomer (e.g., the excipient can be L-leucine or D-leucine).
- the salt formulations can also contain additives, preservatives, or fluid, nutrient or electrolyte replenishers (See, generally, Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Co., PA, 1985).
- the hypertonic calcium salt formulation or calcium salt formulation preferably contains a concentration of calcium salt that permits convenient administration of an effective amount of the formulation to the respiratory tract.
- liquid formulations not be so dilute so as to require a large amount of the formulation to be nebulized in order to deliver an effective amount to the respiratory tract of a subject.
- a liquid hypertonic calcium salt formulation can contain about 1.3% to about 13% calcium salt, such as calcium chloride (w/v).
- Liquid formulations can contain about 0.12M to about 1.2M calcium chloride.
- Liquid calcium salt formulations of this type can vary in the degree of
- the calcium salt formulation can contain 0.212 M CaCl 2 and 0.027 M NaCl (2.35% CaCl 2, 0.16% NaCl), or 0.424 M CaCl 2 and 0.054 M NaCl (4.70% CaCl 2, 0.31% NaCl).
- the calcium salt formulation is selected so that at least about 4 mL or at least about 5 mL of the formulation is aerosolized (e.g., nebulized) during administration.
- at least 4 mL of the calcium salt formulation are aerosolized (e.g., nebulized) during a single administration, and the calcium salt formulation is administered, one, two, three or four times per day.
- the hypertonic calcium salt formulation has at least about 1. IX tonicity, at least about 1.5X tonicity, at least about 2X tonicity, at least about 3X tonicity, at least about 4X tonicity, at least about 5X tonicity, at least about 6X tonicity, at least about 7X tonicity, at least about 8X tonicity, at least about 9X tonicity, at least about 10X tonicity or at least about 1 IX tonicity.
- Dry powder formulations can contain at least about 10% calcium salt by weight, at least about 20%> calcium salt by weight, at least about 30%> calcium salt by weight, at least about 40%) calcium salt by weight, at least about 50%> calcium salt by weight, at least about 60%) calcium salt by weight, at least about 70%> calcium salt by weight, at least about 75% calcium salt by weight, at least about 80%> calcium salt by weight, at least about 85% calcium salt by weight, at least about 90%> calcium salt by weight, at least about 95% calcium salt by weight, at least about 96%> calcium salt by weight, at least about 97% calcium salt by weight, at least about 98% calcium salt by weight, or at least about 99% calcium salt by weight.
- some dry powder formulations contain about 20% to about 80% calcium salt by weight, about 20% to about 70% calcium salt by weight, about 20% to about 60% calcium salt by weight, or can consist substantially of calcium salt(s).
- the hypertonic calcium salt formulation or calcium salt formulation can include one or more additional therapeutic agents, such as mucoactive or mucolytic agents, surfactants, antibiotics, antivirals, antihistamines, cough suppressants, bronchodilators, anti- inflammatory agents, steroids, vaccines, adjuvants, expectorants, macromolecules, therapeutics that are helpful for chronic maintenance of CF.
- additional therapeutic agents such as mucoactive or mucolytic agents, surfactants, antibiotics, antivirals, antihistamines, cough suppressants, bronchodilators, anti- inflammatory agents, steroids, vaccines, adjuvants, expectorants, macromolecules, therapeutics that are helpful for chronic maintenance of CF.
- the additional agent can be blended with a dry powder or co-spray dried as desired.
- mucoactive or mucolytic agents examples include MUC5AC and MUC5B mucins, DNA-ase, N-acetylcysteine (NAC), cysteine, nacystelyn, dornase alfa, gelsolin, heparin, heparin sulfate, P2Y2 agonists (e.g. UTP, INS365), nedocromil sodium, hypertonic saline, and mannitol.
- MUC5AC and MUC5B mucins DNA-ase
- N-acetylcysteine (NAC) N-acetylcysteine
- cysteine eine
- nacystelyn dornase alfa
- gelsolin gelsolin
- heparin heparin
- heparin sulfate examples include P2Y2 agonists (e.g. UTP, INS365), nedocromil sodium
- Suitable surfactants include L-alpha-phosphatidylcholine dipalmitoyl ("DPPC"), diphosphatidyl glycerol (DPPG), l,2-Dipalmitoyl-sn-glycero-3-phospho-L-serine (DPPS), 1 ,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DSPC), 1 ,2-Distearoyl-sn-glycero-3- phosphoethanolamine (DSPE), l-palmitoyl-2-oleoylphosphatidylcholine (POPC), fatty alcohols, polyoxyethylene-9-lauryl ether, surface active fatty, acids, sorbitan trioleate (Span 85), glycocholate, surfactin, poloxomers, sorbitan fatty acid esters, tyloxapol, phospholipids, and alkylated sugars.
- DPPC L-alpha-phosphatidylcholine dipal
- the salt formulation can contain an antibiotic.
- the antibiotic can be suitable for treating any desired bacterial infection, and salt formulations that contain an antibiotic can be used to reduce the spread of infection, either within a patient or from patient to patient.
- salt formulations for treating bacterial pneumonia or VAT can further comprise an antibiotic, such as a macrolide (e.g., azithromycin, clarithromycin and erythromycin), a tetracycline (e.g., doxycycline, tigecycline), a fluoroquinolone (e.g., gemifloxacin, levofloxacin, ciprofloxacin and mocifloxacin), a cephalosporin (e.g., ceftriaxone, defotaxime, ceftazidime, cefepime), a penicillin (e.g., amoxicillin, amoxicillin with clavulanate, ampicillin, piperacillin, and ticarcillin) optionally with an antibiotic, such as
- a monobactam e.g., aztreonam
- an oxazolidinone e.g., linezolid
- vancomycin e.g., glycopeptide antibiotics (e.g. telavancin)
- the salt formulation can contain an agent for treating infections with mycobacteria, such as Mycobacterium tuberculosis.
- agents for treating infections with mycobacteria include an aminoglycoside (e.g. capreomycin, kanamycin, streptomycin), a fluoroquinolone (e.g. ciprofloxacin, levofloxacin, moxifloxacin), isozianid and isozianid analogs (e.g. ethionamide), aminosalicylate, cycloserine, diarylquinoline, ethambutol, pyrazinamide, protionamide, rifampin, and the like.
- aminoglycoside e.g. capreomycin, kanamycin, streptomycin
- a fluoroquinolone e.g. ciprofloxacin, levofloxacin, moxifloxacin
- isozianid and isozianid analogs e.
- the salt formulation can contain a suitable antiviral agent, such as oseltamivir, zanamavir, amantidine, rimantadine, ribavirin, gancyclovir, valgancyclovir, foscavir, Cytogam® (Cytomegalovirus Immune Globulin), pleconaril, rupintrivir, palivizumab, motavizumab, cytarabine, docosanol, denotivir, cidofovir, and acyclovir.
- the salt formulation can contain a suitable anti-influenza agent, such as zanamivir, oseltamivir, amantadine, or rimantadine.
- Suitable antihistamines include clemastine, asalastine, loratadine, fexofenadine and the like.
- Suitable cough suppressants include benzonatate, benproperine, clobutinal, diphenhydramine, dextromethorphan, dibunate, fedrilate, glaucine, oxalamine, piperidione, opiods such as codeine and the like.
- Suitable brochodilators include short-acting beta 2 agonists, long-acting beta 2 agonists (LABA), long-acting muscarinic anagonists (LAMA), combinations of LABAs and LAMAs, methylxanthines, short-acting anticholinergic agents (may also be referred to as short acting anti-muscarinic), and the like.
- Suitable short-acting beta 2 agonists include albuterol, epinephrine, pirbuterol, levalbuterol, metaproteronol, maxair, and the like.
- albuterol sulfate formulations include Inspiryl (AstraZeneca Pic), Salbutamol SANDOZ (Sanofi-Aventis), Asmasal clickhaler (Vectura Group Pic), Ventolin ® (Glaxo SmithKline Pic), Salbutamol GLAND (Glaxo SmitfiKline Pic), Airomir ® (Teva Pharmaceutical Industries Ltd.), ProAir HFA (Teva Pharmaceutical Industries Ltd.), Salamol (Teva Pharmaceutical Industries Ltd.), Ipramol (Teva Pharmaceutical Industries Ltd), Albuterol sulfate TEVA (Teva Pharmaceutical Industries Ltd), and the like.
- Inspiryl AstraZeneca Pic
- Salbutamol SANDOZ Sanofi-Aventis
- Asmasal clickhaler Vectura Group Pic
- Ventolin ® Gaxo SmithKline Pic
- Salbutamol GLAND Gaxo SmitfiKline Pic
- Airomir ® Teva Pharmaceutical Industries Ltd.
- ProAir HFA Teva Pharmaceutical Industries Ltd.
- Examples of epinephrine include Epinephine Mist KING (King Pharmaceuticals, Inc.), and the like.
- Examples of pirbuterol as pirbuterol acetate include Maxair® (Teva Pharmaceutical Industries Ltd.), and the like.
- Examples of levalbuterol include Xopenex ® (Sepracor), and the like.
- Examples of metaproteronol formulations as metaproteronol sulfate include Alupent ® (Boehringer Ingelheim GmbH), and the like.
- Suitable LABAs include salmeterol, formoterol and isomers thereof (e.g. arformoterol), clenbuterol, tulobuterol, vilanterol (RevolairTM), indacaterol, carmoterol, isoproterenol, procaterol, bambuterol, milveterol, olodaterol and the like.
- salmeterol formoterol and isomers thereof (e.g. arformoterol), clenbuterol, tulobuterol, vilanterol (RevolairTM), indacaterol, carmoterol, isoproterenol, procaterol, bambuterol, milveterol, olodaterol and the like.
- salmeterol formulations include salmeterol xinafoate as Serevent ® (Glaxo SmithKline Pic), salmeterol as Inaspir (Laboratorios Almirall, S.A.), Advair ® HFA (Glaxo SmithKline PLC), Advair Diskus ® (Glaxo SmithKline PLC, Therassemble Inc), Plusvent (Laboratorios Almirall, S.A.), VR315 (Novartis, Vectura Group PLC) and the like.
- Examples of formoterol and isomers formulations include Foster (Chiesi Farmaceutici S.p.A), Atimos (Chiesi Farmaceutici S.p.A, Ny corned Internaional Management), Flutiform ® (Abbott Laboratories, SkyePharma PLC), MFF258 (Novartis AG), Formoterol clickhaler (Vectura Group PLC), Formoterol HFA (SkyePharma PLC), Oxis ® (Astrazeneca PLC), Oxis pMDI (Astrazeneca), Foradil ® Aerolizer (Novartis, Schering- Plough Corp, Merck), Foradil ® Certihaler (Novartis, SkyePharma PLC), Symbicort ® (AstraZeneca), VR632 (Novartis AG, Sandoz International GmbH), MFF258 (Merck & Co Inc, Novartis), MFF258 (Merck & Co Inc
- clenbuterol formulations include Ventipulmin ® (Boehringer Ingelheim), and the like.
- tulobuterol formulations include Hokunalin Tape (Abbott Japan Co., Ltd., Maruho Co., Ltd.), and the like.
- vilanterol formulations include RevolairTM (GlaxoSmithKline PLC), GSK64244 (Glaxo SmithKline PLC), and the like.
- indacaterol formulations include QAB149 (Novartis AG, SkyePharma PLC), QMF149 (Merck & Co Inc) and the like.
- carmoterol formulations examples include CHF4226 (Chiese Farmaceutici S.p.A., Mitsubishi Tanabe Pharma Corporation), CHF5188 (Chiesi Farmaceutici S.p.A), and the like.
- isoproterenol sulfate formulations examples include Aludrin (Boehringer Ingelheim GmbH) and the like.
- procaterol formulations examples include Meptin clickhaler (Vectura Group PLC), and the like.
- bambuterol formulations examples include Bambec (AstraZeneca PLC), and the like.
- milveterol formulations examples include GSK159797C (GlaxoSmithKline PLC), TD3327 (Therassemble Inc), and the like.
- olodaterol formulations examples include BI1744CL (Boehringer Ingelheim GmbH) and the like.
- LAMAs examples include tiotroprium, trospium chloride, glycopyrrolate, aclidinium, ipratropium and the like.
- Examples of tiotroprium formulations include Spiriva ® (Boehringer-Ingleheim, Pfizer), and the like.
- Examples of glycopyrrolate formulations include Robinul ® (Wyeth- Ayerst), Robinul ® Forte (Wyeth-Ayerst), NVA237 (Novartis), and the like.
- Examples of aclidinium formulations include Eklira ® (Forest Labaoratories, Almirall), and the like.
- Examples of combinations of LABAs and LAMAs include indacaterol with glycopyrrolate, formoterol with glycopyrrolate, indacaterol with tiotropium, olodaterol and tiotropium, vilanterol with a LAMA, and the like.
- Examples of combinations of indacaterol with glycopyrrolate include QVA149A (Novartis), and the like.
- Examples of combinations of formoterol with glycopyrrolate include PT003 (Pearl Therapeutics) and the like.
- Examples of combinations of olodaterol with tiotropium include BI1744 with Spiriva (Boehringer Ingelheim) and the like.
- Examples of combinations of vilanterol with a LAMA include GSK573719 with GSK642444 (GlaxoSmithKline PLC), and the like.
- methylxanthines examples include aminophylline, ephedrine, theophylline, oxtriphylline, and the like.
- aminophylline formulations include Aminophylline BOEHRINGER (Boehringer Ingelheim GmbH) and the like.
- ephedrine formulations include Bronkaid ® (Bayer AG), Broncholate (Sanofi-Aventis), Primatene ® (Wyeth), Tedral SA ® , Marax (Pfizer Inc) and the like.
- theophylline formulations include Euphyllin (Nycomed International Management GmbH), Theo-dur (Pfizer Inc, Teva Pharmacetuical Industries Ltd) and the like.
- oxtriphylline formulations include Choledyl SA (Pfizer Inc) and the like.
- Examples of short-acting anticholinergic agents include ipratropium bromide, oxitropium bromide, and tiotropium (Spiriva).
- ipratropium bromide formulations include Atrovent ® /Apovent/Inpratropio (Boehringer Ingelheim GmbH), Ipramol (Teva Pharmaceutical Industries Ltd) and the like.
- oxitropium bromide examples include Oxivent (Boehringer Ingelheim GmbH), and the like.
- Suitable anti-inflammatory agents include leukotriene inhibitors, phosphodiesterase 4 (PDE4) inhibitors, other anti-inflammatory agents, and the like.
- Suitable leukotriene inhibitors include montelukast (cystinyl leukotriene inhibitors), masilukast, zafirleukast (leukotriene D4 and E4 receptor inhibitors), pranlukast, zileuton (5 -lipoxygenase inhibitors), and the like.
- Examples of montelukast formulations include Singulair ® (Merck & Co Inc), Loratadine, montelukast sodium SCHERING (Schering- Plough Corp), MK0476C (Merck & Co Inc), and the like.
- Examples of masilukast formulations include MCC847 (AstraZeneca PLC), and the like.
- Examples of zafirlukast formulations include Accolate ® (AstraZeneca PLC), and the like.
- Examples of pranlukast formulations include Azlaire (Schering-Plough Corp).
- zileuton (5-LO) formulations examples include Zyflo ® (Abbott Laboratories), Zyflo CR ® (Abbott Laboratories, SkyePharma PLC), Zileuton ABBOTT LABS (Abbott Laboratories), and the like.
- Suitable PDE4 inhibitors include cilomilast, roflumilast, oglemilast, tofimilast, and the like.
- Examples of cilomilast formulations include Ariflo (Glaxo SmithKline PLC), and the like.
- examples of roflumilast include Daxas ® (Nycomed International Management GmbH, Pfizer Inc), APTA2217 (Mitsubishi Tanabe Pharma Corporation), and the like.
- Examples of oglemilast formulations include GRC3886 (Forest Laboratories Inc), and the like.
- Examples of tofimilast formulations include Tofimilast PFIZER INC (Pfizer Inc), and the like.
- anti-inflammatory agents include omalizumab (anti-IgE immunoglobulin Daiichi Sankyo Company, Limited), Zolair (anti-IgE immunoglobulin, Genentech Inc, Novartis AG, Roche Holding Ltd), Solfa (LTD4 antagonist and phosphodiesterase inhibitor, Takeda Pharmaceutical Company Limited), IL-13 and IL-13 receptor inhibitors (such as AMG-317, MILR1444A, CAT-354, QAX576, IMA-638, Anrukinzumab, IMA-026, MK- 6105,DOM-0910, and the like), IL-4 and IL-4 receptor inhibitors (such as Pitrakinra, AER- 003,AIR-645, APG-201, DOM-0919, and the like), IL-1 inhibitors such as canakinumab, CRTh2 receptor antagonists such as AZD1981 (CRTh2 receptor antagonist, AstraZeneca), neutrophil elastase inhibitor formulations such as
- Anti-inflammatory agents also include compounds that inhibit/decrease cell signaling by inflammatory molecules like cytokines (e.g., IL-1, IL-4, IL-5, IL-6, IL-9, IL-13, IL-18 IL-25, IFN-a, IFN- ⁇ , and others), CC chemokines CCL-1 - CCL28 (some of which are also known as, for example, MCP-1, CCL2, RANTES), CXC chemokines CXCL1 - CXCL17 (some of which are also know as, for example, IL-8, MIP-2), growth factors (e.g., GM-CSF, NGF, SCF, TGF- ⁇ , EGF, VEGF and others) and/or their respective receptors.
- cytokines e.g., IL-1, IL-4, IL-5, IL-6, IL-9, IL-13, IL-18 IL-25, IFN-a, IFN- ⁇ , and others
- Some examples of the aforementioned anti-inflammatory antagonists/inhibitors include ABN912 (MCP-1/CCL2, Novartis AG), AMG761 (CCR4, Amgen Inc), Enbrel ® (TNF, Amgen Inc, Wyeth), huMAb OX40L GENENTECH (TNF superfamily, Genentech Inc, AstraZeneca PLC), R4930 (TNF superfamily, Roche Holding Ltd), SB683699/Firategrast (VLA4, GlaxoSmithKline PLC), CNT0148 (TNFa, Centocor, Inc, Johnson & Johnson, Schering-Plough Corp); Canakinumab (IL- ⁇ , Novartis); Israpafant MITSUBISHI (PAF/IL-5, Mitsubishi Tanabe Pharma Corporation); IL-4 and IL-4 receptor antagonists/inhibitors: AMG317 (Amgen Inc), BAY 169996 (Bayer AG), AER-003 (Aerovance), APG-201 (
- Suitable steroids include corticosteroids, combinations of corticosteroids and LABAs, combinations of corticosteroids and LAMAs, combinations of corticosteroids with LABAs and LAMAs, and the like.
- Suitable corticosteroids include budesonide, fluticasone, flunisolide, triamcinolone, beclomethasone, mometasone, ciclesonide, dexamethasone, and the like.
- Examples of budesonide formulations include Captisol-Enabled ® Budesonide Solution for Nebulization (AstraZeneca PLC), Pulmicort ® (AstraZeneca PLC), Pulmicort ® Flexhaler (AstraZeneca Pic), Pulmicort ® HFA-MDI (AstraZeneca PLC), Pulmicort Respules ® (AstraZeneca PLC), Inflammide (Boehringer Ingelheim GmbH), Pulmicort ® HFA-MDI (SkyePharma PLC), Unit Dose Budesonide ASTRAZENECA (AstraZeneca PLC), Budesonide Modulite (Chiesi Farmaceutici S.p.A), CHF5188 (Chiesi Farmaceutici S.p.A), Budesonide ABBOTT LABS (Abbott Laboratories), Budesonide clickhaler (Vestura Group PLC), Mifionide (No
- fluticasone propionate formulations include Flixotide Evohaler (GlaxoSmithKline PLC), Flixotide Nebules (Glaxo SmithKline Pic), Flovent ® (GlaxoSmithKline Pic), Flovent ® Diskus (GlaxoSmithKline PLC), Flovent ® HFA (GlaxoSmithKline PLC), Flovent ® Rotadisk (GlaxoSmithKline PLC), Advair ® HFA (GlaxoSmithKline PLC, Therassemble Inc), Advair Diskus ® (GlaxoSmithKline PLC, Therassemble Inc.), VR315 (Novartis AG, Vectura Group PLC, Sandoz International GmbH), and the like.
- fluticasone as Flusonal (Laboratorios Almirall, S.A.), fluticasone furoate as GW685698 (GlaxoSmithKline PLC, Thervance Inc.), Plusvent (Laboratorios Almirall, S.A.), Flutiform ® (Abbott Laboratories, SkyePharma PLC), and the like.
- Examples of fiunisolide formulations include Aerobid ® (Forest Laboratories Inc), Aerospan ® (Forest Laboratories Inc), and the like.
- Examples of triamcinolone formulations include Triamcinolone ABBOTT LABS (Abbott Laboratories), Azmacort ® (Abbott Laboratories, Sanofi-Aventis), and the like.
- beclomethasone dipropionate formulations examples include Beclovent (GlaxoSmithKline PLC), QVAR ® (Johnson & Johnson, Schering-Plough Corp, Teva Pharmacetucial Industries Ltd), Asmabec clickhaler (Vectura Group PLC), Beclomethasone TEVA (Teva Pharmaceutical Industries Ltd), Vanceril (Schering-Plough Corp), BDP Modulite (Chiesi Farmaceutici S.p.A.), Clenil (Chiesi Farmaceutici S.p.A), Beclomethasone dipropionate TEVA (Teva Pharmaceutical Industries Ltd), and the like.
- mometasone examples include QAB149 Mometasone furoate (Schering-Plough Corp), QMF149 (Novartis AG), Fomoterol fumarate, mometoasone furoate (Schering-Plough Corp), MFF258 (Novartis AG, Merck & Co Inc), Asmanex ® Twisthaler (Schering-Plough Corp), and the like.
- Examples of cirlesonide formulations include Alvesco ® (Nycomed International Management GmbH, Sepracor, Sanofi-Aventis, Tejin Pharma Limited), Alvesco Combo (Nycomed International Management GmbH, Sanofi- Aventis), Alvesco ® HFA (Nycomed Intenational Management GmbH, Sepracor Inc), and the like.
- Examples of dexamethasone formulations include DexPak ® (Merck), Decadron ® (Merck), Adrenocot, CPC-Cort-D, Decaject-10, Solurex and the like.
- Other corticosteroids include Etiprednol dicloacetate TEVA (Teva Pharmaceutical Industries Ltd), and the like.
- Combinations of corticosteroids and LABAs include salmeterol with fluticasone, formoterol with budesonide, formoterol with fluticasone, formoterol with mometasone, indacaterol with mometasone, and the like.
- Examples of salmeterol with fluticasone include Plusvent (Laboratorios Almirall, S.A.), Advair ® HFA (Glaxo SmithKline PLC), Advair ® Diskus (Glaxo SmithKline PLV, Therassemble Inc), VR315 (Novartis AG, Vectura Group PLC, Sandoz International GmbH) and the like.
- Examples of vilanterol with fluticasone include GSK642444 with fluticasone and the like.
- Examples of formoterol with budesonide include Symbicort ® (AstraZeneca PLC), VR632 (Novartis AG, Vectura Group PLC), and the like.
- Examples of formoterol with fluticasone include Flutiform ® (Abbott Laboratories, SkyePharma PLC), and the like.
- Examples of formoterol with mometasone include Dulera ® /MFF258 (Novartis AG, Merck & Co Inc), and the like.
- Examples of indacaterol with mometasone include QAB149 Mometasone furoate (Schering-Plough Corp), QMF149 (Novartis AG), and the like.
- Combinations of corticosteroids with LAMAs include fluticasone with tiotropium, budesonide with tiotropium, mometasone with tiotropium, salmeterol with tiotropium, formoterol with tiotropium, indacaterol with tiotropium, vilanterol with tiotropium, and the like.
- Combinations of corticosteroids with LAMAs and LABAs include fluticasone with salmeterol and tiotropium.
- anti-asthma molecules include: ARD111421 (VIP agonist, AstraZeneca PLC), AVE0547 (anti-inflammatory, Sanofi-Aventis), AVE0675 (TLR agonist, Pfizer, Sanofi-Aventis), AVE0950 (Syk inhibitor, Sanofi-Aventis), AVE5883 (NK1/NK2 antagonist, Sanofi-Aventis), AVE8923 (tryptase beta inhibitor, Sanofi-Aventis), CGS21680 (adenosine A2A receptor agonist, Novartis AG), ATL844 (A2B receptor antagonist, Novartis AG), BAY443428 (tryptase inhibitor, Bayer AG), CHF5407 (M3 receptor inhibitor, Chiesi Farmaceutici S.p.A.), CPLA2 Inhibitor WYETH (CPLA2 inhibitor, Wyeth), IMA-638 (IL-13 antagonist, Wyeth), LAS 100977 (
- AstraZeneca PLC AZD1744 (CCR3/histamine-l receptor antagonist, AZD1419 (TLR9 agonist), Mast Cell inhibitor ASTRAZENECA, AZD3778 (CCR antagonist), DSP3025 (TLR7 agonist), AZD1981 (CRTh2 receptor antagonist), AZD5985 (CRTh2 antagonist), AZD8075 (CRTh2 antagonist), AZD1678, AZD2098, AZD2392, AZD3825 AZD8848, AZD9215, ZD2138 (5-LO inhibitor), AZD3199 (LABA);
- GlaxoSmithKline PLC GW328267 (adenosine A2 receptor agonist), GW559090 (a4 integrin antagonist), GSK679586 (mAb), GSK597901 (adrenergic ⁇ 2 agonist), AM103 (5-LO inhibitor), GSK256006 (PDE4 inhibitor), GW842470 (PDE-4 inhibitor), GSK870086 (glucocorticoid agonist), GSK159802 (LABA), GSK256066 (PDE- 4 inhibitor), GSK642444 (LABA, adrenergic ⁇ 2 agonist), GSK64244 and Revolair (fluticasone/vilanterol), GSK799943 (corticosteroid), GSK573719 (mAchR antagonist), and GSK573719.
- GW328267 adenosine A2 receptor agonist
- GW559090 a4 integrin antagonist
- GSK679586 mAb
- GSK597901 adren
- Pfizer Inc PF3526299, PF3893787, PF4191834 (FLAP antagonist), PF610355 (adrenergic ⁇ 2 agonist), CP664511 (a4pl/VCAM-l interaction inhibitor), CP609643 (inhibitor of ⁇ 4 ⁇ 1/VCAM-l interactions), CP690550 (JAK3 inhibitor), SAR21609 (TLR9 agonist), AVE7279 (Thl switching), TBC4746 (VLA-4 antagonist); R343 (IgE receptor signaling inhibitor), SEP42960 (adenosine A3 antagonist);
- Sanofi-Aventis MLN6095 (CrTH2 inhibitor), SAR137272 (A3 antagonist), SAR21609 (TLR9 agonist), SAR389644 (DPI receptor antagonist), SAR398171 (CRTH2 antagonist), SSR161421 (adenosine A3 receptor antagonist);
- Suitable expectorants include guaifenesin, guaiacolculfonate, ammonium chloride, potassium iodide, tyloxapol, antimony pentasulfide and the like.
- Suitable vaccines include nasally inhaled influenza vaccines and the like.
- Suitable macromolecules include proteins and large peptides, polysaccharides and oligosaccharides, and DNA and RNA nucleic acid molecules and their analogs having therapeutic, prophylactic or diagnostic activities. Proteins can include antibodies such as monoclonal antibodies. Nucleic acid molecules include genes, antisense molecules such as siRNAs that bind to complementary DNA, RNAi, shRNA, microRNA, RNA, or ribosomes to inhibit transcription or translation. Preferred macromolecules have a molecular weight of at least 800 Da, at least 3000 Da or at least 5000 Da.
- Selected macromolecule drugs for systemic applications Ventavis (Iloprost), Calcitonin, Erythropoietin (EPO), Factor IX, Granulocyte Colony Stimulating Factor (G- CSF), Granulocyte Macrophage Colony, Stimulating Factor (GM-CSF), Growth Hormone, Insulin, Interferon Alpha, Interferon Beta, Interferon Gamma, Luteinizing Hormone Releasing Hormone (LHRH), follicle stimulating hormone (FSH), Ciliary Neurotrophic Factor, Growth Hormone Releasing Factor (GRF), Insulin-Like Growth Factor, Insulinotropin, Interleukin-1 Receptor Antagonist, Interleukin-3, Interleukin-4, Interleukin-6, Macrophage Colony Stimulating Factor (M-CSF), Thymosin Alpha 1, Ilb/IIIa Inhibitor, Alpha- 1 Antitrypsin, Anti-RSV Anti
- GLP-1 analogs (liraglutide, exenatide, etc.), Domain antibodies (dAbs), Pramlintide acetate (Symlin), Leptin analogs, Synagis (palivizumab, Medlmmune) and cisplatin.
- Selected therapeutics helpful for chronic maintenance of CF include antibiotics/macrolide antibiotics, bronchodilators, inhaled LABAs, and agents to promote airway secretion clearance.
- antibiotics/macrolide antibiotics include tobramycin, azithromycin, ciprofloxacin, colistin, aztreonam and the like.
- Another exemplary antibiotic/macro lide is levofloxacin.
- Suitable examples of bronchodilators include inhaled short-acting beta 2 agonists such as albuterol, and the like.
- Suitable examples of inhaled LABAs include salmeterol, formoterol, and the like.
- agents to promote airway secretion clearance include Pulmozyme (dornase alfa, Genetech), hypertonic saline, DNase, heparin and the like.
- Selected therapeutics helpful for the prevention and/or treatment of CF include VX-770 (Vertex Pharmaceuticals) and amiloride.
- Selected therapeutics helpful for the treatment of idiopathic pulmonary fibrosis include Metelimumab (CAT- 192) (TGF- ⁇ 1 mAb inhibitor, Genzyme), Aerovant TM (AER001, pitrakinra) (Dual IL-13, IL-4 protein antagonist, Aerovance), Aeroderm (PEGylated Aerovant, Aerovance), microR A, RNAi, and the like.
- the respirable dry powder or respirable dry particle comprises an antibiotic, such as a macro lide (e.g., azithromycin, clarithromycin and erythromycin), a tetracycline (e.g., doxycycline, tigecycline), a fluoroquinolone (e.g., gemifloxacin, levofloxacin, ciprofloxacin and mocifloxacin), a cephalosporin (e.g., ceftriaxone, defotaxime, ceftazidime, cefepime), a penicillin (e.g., amoxicillin, amoxicillin with clavulanate, ampicillin, piperacillin, and ticarcillin) optionally with a ⁇ -lactamase inhibitor (e.g., sulbactam, tazobactam and clavulanic acid), such as ampicillin-sulbactam, piperacillin-t
- an antibiotic such as a
- the respirable dry powder or respirable dry particle comprises levofloxacin.
- the respirable dry powder or respirable dry particle comprises Cayston®.
- the respirable dry powder or respirable dry particle does not comprise tobramycin.
- the respirable dry powder or respirable dry particle does not comprise levofloxacin.
- the respirable dry powder or respirable dry particle does not comprise Cayston®.
- the salt formulation can contain an agents that disrupt and/or disperse bio films.
- agents to promote disruption and/or dispersion of bio films include specific amino acid stereoisomers, e.g. D-leucine, D-methionine, D-tyrosine, D- tryptophan, and the like.
- D-leucine e.g. D-leucine
- D-methionine e.g. D-methionine
- D-tyrosine e.g. D-methionine
- D- tryptophan e.g. D-leucine
- D-methionine e.g. D-methionine
- D-tyrosine D- tryptophan
- dry powder formulations are prepared with the appropriate particle diameter, surface roughness, and tap density for localized delivery to selected regions of the respiratory tract. For example, higher density or larger particles may be used for upper airway delivery. Similarly, a mixture of different sized particles can be administered to target different regions of the
- the phrase "aerodynamically light particles” refers to respirable particles having a tap density less than about 0.4 g/cm 3 .
- the tap density of particles of a dry powder may be obtained by the standard USP tap density measurement. Tap density is an accepted, approximate measure of the envelope mass density.
- the envelope mass density of an isotropic particle is defined as the mass of the particle divided by the minimum sphere envelope volume in which it can be enclosed. Additional features contributing to low tap density include irregular surface texture and porous structure.
- Dry powder formulations with large particle size have improved flowability characteristics, such as less aggregation (Visser, J., Powder Technology 58: 1-10 (1989)), easier aerosolization, and potentially less phagocytosis. Rudt, S. and R. H. Muller. J. Controlled Release, 22: 263-272 (1992); Tabata Y., and Y. Ikada. J. Biomed. Mater. Res. 22: 837-858 (1988). Dry powder aerosols for inhalation therapy are generally produced with mass median aerodynamic diameters primarily in the range of less than 5 microns, although dry powders that have any desired range in aerodynamic diameter can be produced.
- salt formulations that are dry powders may be produced by spray drying, freeze drying, spray- freeze drying jet milling, single and double emulsion solvent evaporation, and supercritical fluid-based processes, among others.
- salt formulations are produced by spray drying, which entails preparing a solution containing the salt and other components of the formulation, spraying the solution into a closed chamber, and removing the solvent with a heated gas stream. Suitable spray-drying techniques are described, for example, by K. Masters in "Spray Drying Handbook", John Wiley & Sons, New York (1984).
- heat from a hot gas such as heated air or nitrogen is used to evaporate a solvent from droplets formed by atomizing a continuous liquid feed.
- a hot gas such as heated air or nitrogen
- the moisture in the air is at least partially removed before its use.
- nitrogen gas can be run “dry”, meaning that no additional water vapor is combined with the gas. If desired the moisture level of the nitrogen or air can be set before the beginning of spry dry run at a fixed value above "dry" nitrogen.
- the spray drying or other instruments used to prepare the dry particles can include an inline geometric particle sizer that determines a geometric diameter of the respirable dry particles as they are being produced, and/or an inline aerodynamic particle sizer that determines the aerodynamic diameter of the respirable dry particles as they are being produced.
- Spray dried powders that contain salts with sufficient solubility in water or aqueous solvents, such as calcium chloride and calcium lactate can be readily prepared using conventional methods. Some salts, such as calcium citrate and calcium carbonate, have low solubility in water and other aqueous solvents. Spray dried powders that contain such salts can be prepared using any suitable method. One suitable method involves combining other more soluble salts in solution and permitting reaction (precipitation reaction) to produce the desired salt for the dry powder formulation. For example, if a dry powder formulation comprising calcium citrate and sodium chloride is desired, a solution containing the high solubility salts calcium chloride and sodium citrate can be prepared.
- the precipitation reaction leading to calcium citrate is 3 CaCl 2 + 2 Na 3 Cit ⁇ Ca 3 Cit 2 + 6 NaCl. It is preferable that the sodium salt is fully dissolved before the calcium salt is added and that the solution is continuously stirred.
- the precipitation reaction can be allowed to go to completion or stopped before completion, e.g., by spray drying the solution, as desired.
- the resulting solution may appear clear with fully dissolved salts or a precipitate may form.
- a precipitate may form quickly or over time. Solutions that contain a light precipitate that results in formation of a stable homogenous suspension can be spray dried.
- two saturated or sub-saturated solutions are fed into a static mixer in order to obtain a saturated or supersaturated solution post-static mixing.
- the post-spray drying solution is supersaturated.
- the two solutions may be aqueous or organic, but are preferably substantially aqueous.
- the post-static mixing solution is then fed into the atomizing unit of a spray dryer.
- the post-static mixing solution is immediately fed into the atomizer unit.
- Some examples of an atomizer unit include a two- fluid nozzle, a rotary atomizer, or a pressure nozzle.
- the atomizer unit is a two- fluid nozzle.
- the two-fluid nozzle is an internally mixing nozzle, meaning that the gas impinges on the liquid feed before exiting to most outward orifice. In another embodiment, the two-fluid nozzle is an externally mixing nozzle, meaning that the gas impinges on the liquid feed after exiting the most outward orifice.
- Dry powder formulations can also be prepared by blending individual components into the final formulation. For example, a first dry powder that contains a calcium salt can be blended with a second dry powder that contains a sodium salt to produce a dry powder salt formulation that contains a calcium salt and a sodium salt. If desired, additional dry powders that contain excipients ⁇ e.g., lactose) and/or other active ingredients ⁇ e.g., antibiotic, antiviral) can be included in the blend. The blend can contain any desired relative amounts or ratios of salts, excipients and other ingredients ⁇ e.g., antibiotics, antivirals).
- dry powders can be prepared using polymers that are tailored to optimize particle characteristics including: i) interactions between the agent ⁇ e.g., salt) to be delivered and the polymer to provide stabilization of the agent and retention of activity upon delivery; ii) rate of polymer degradation and thus agent release profile; iii) surface characteristics and targeting capabilities via chemical modification; and iv) particle porosity.
- Polymeric particles may be prepared using single and double emulsion solvent evaporation, spray drying, solvent extraction, solvent evaporation, phase separation, simple and complex coacervatian, interfacial polymerization, and other methods well known to those of ordinary skill in the art.
- Particles may be made using methods for making microspheres or microcapsules known in the art.
- compositions of some preferred salt compositions are presented in Table 1.
- the compositions disclosed in Table 1 are non-limiting examples of salt compositions that can be administered in accordance with the methods of the invention.
- the weight percentages of the dry powder formulations are on a dry basis.
- Respirable dry powder calcium salt formulations are preferred for use in the invention.
- the dry powder administered in the methods described herein contains respirable dry particles that contain i) about 20% (w/w) leucine, ii) about 75% (w/w) calcium lactate, and iii) about 5% (w/w) sodium chloride.
- the dry powder administered in the methods described herein contains respirable dry particles that contain i) about 37.5%) (w/w) leucine, ii) about 58.6%> (w/w) calcium lactate, and iii) about 3.9% (w/w) sodium chloride.
- the weight percentages are on a dry basis.
- respirable dry powders and/or dry particles are based on
- Formulation 29 or 30 and include one or more additional therapeutic agents, such as any of the additional therapeutic agents described herein, e.g., mucoactive or mucolytic agents, surfactants, antibiotics, antivirals, antihistamines, cough suppressants, bronchodilators, antiinflammatory agents, steroids, vaccines, adjuvants, expectorants, macromolecules, or therapeutics that are helpful for chronic maintenance of cystic fibrosis (CF).
- additional therapeutic agents such as any of the additional therapeutic agents described herein, e.g., mucoactive or mucolytic agents, surfactants, antibiotics, antivirals, antihistamines, cough suppressants, bronchodilators, antiinflammatory agents, steroids, vaccines, adjuvants, expectorants, macromolecules, or therapeutics that are helpful for chronic maintenance of cystic fibrosis (CF).
- the additional agent can be blended with a dry powder of Formulation 29 or 30 or co-spray dried as desired.
- the preferred dry powders can contain dry particles that contain about 20% (w/w) leucine, about 75% (w/w) calcium lactate, and about 5% (w/w) sodium chloride; about 37.5% (w/w) leucine, about 58.6% (w/w) calcium lactate, and about 3.9% (w/w) sodium chloride (e.g, Formulations 29 and 30 respectively), that are blended with an additional therapeutic agent or co-formulated with an additional therapeutic agent.
- Such blended or co-formulated preparations can be produced in a variety of ways.
- respirable dry particles of the invention can be blended with an additional therapeutic agent or the components of Formulation 29 or Formulation 30 can be co-spray dried with an additional therapeutic agent, such as any one or combination of the additional therapeutic agents disclosed herein, to produce a dry powder.
- Blended dry powders contain particles of Formulation 29 and/or 30 and particles that contain an additional therapeutic agent.
- Preferred additional therapeutic agents are LABAs (e.g., formoterol, salmeterol), short-acting beta agonists (e.g., albuterol), corticosteroids (e.g., fluticasone), LAMAs (e.g., tiotropium), antibiotics (e.g., levofloxacin), recombinant human deoxyribonuclease I (e.g., dornase alfa, also known as DNAse), sodium channel blockers (e.g., amiloride), and combinations thereof.
- LABAs e.g., formoterol, salmeterol
- short-acting beta agonists e.g., albuterol
- corticosteroids e.g., fluticasone
- LAMAs e.g., tiotropium
- antibiotics e.g., levofloxacin
- recombinant human deoxyribonuclease I
- Particularly preferred additional therapeutic agents are short-acting beta agonists (e.g., albuterol), antibiotics (e.g., levofloxacin), recombinant human deoxyribonuclease I (e.g., dornase alfa, also known as DNAse), sodium channel blockers (e.g., amiloride), and combinations thereof.
- beta agonists e.g., albuterol
- antibiotics e.g., levofloxacin
- recombinant human deoxyribonuclease I e.g., dornase alfa, also known as DNAse
- sodium channel blockers e.g., amiloride
- Dry powders can be prepared by co-spray drying an additional therapeutic agent with the calcium lactate and sodium chloride components, and optionally all or a portion of the leucine component of Formulation 29 or Formulation 30.
- the additional therapeutic agent can be added to a solution of Formulation 29 or Formulation 30 and the resulting solution spray dried to produce dry particles that contain the additional therapeutic agent. In such particles the amount of calcium lactate, sodium chloride and leucine in the dry particles will each be lower than the amounts in Formulation 29 or 30, due to the addition of the additional therapeutic agent.
- the formulation can contain up to about 20% (w/w) additional therapeutic agent, and the amount of each of calcium lactate, sodium chloride and leucine are reduced proportionally, but the ratio of the amounts (wt%) of calcium lactate: sodium chloride: leucine is the same as in Formulation 29 or 30.
- the formulation can contain up to about 6% (w/w) additional therapeutic agent.
- the formulation can contain up to about 1% (w/w) additional therapeutic agent.
- the dry particles are based on Formulation 29 and contain up to about 6% (w/w) of one or more additional therapeutic agents, about 70% to about 75%) (w/w) calcium lactate, about 3% to about 5% (w/w) sodium chloride and about 17% to about 20% (w/w) leucine.
- the dry particles are based on Formulation 30 and contain up to about 6% (w/w) of one or more additional therapeutic agent, about 45% to about 58.6%> (w/w) calcium lactate, about 1.9% to about 3.9%) (w/w) sodium chloride and about 30% to about 37.5% (w/w) leucine.
- the dry particles are based on Formulation 29 and contain up to about 20%) (w/w) of one or more additional therapeutic agents, about 60% to about 75% (w/w) calcium lactate, about 2% to about 5% (w/w) sodium chloride and about 15% to about 20% (w/w) leucine. In other exemplary embodiments, the dry particles are based on
- Formulation 30 and contain up to about 20% (w/w) of one or more additional therapeutic agent, about 54.6% to about 58.6% (w/w) calcium lactate, about 1.9% to about 3.9% (w/w) sodium chloride and about 34.5% to about 37.5% (w/w) leucine.
- additional therapeutic agent When the additional therapeutic agent is potent, a small amount may be used such as 0.01% to about 1% (w/w), and the composition of the dry particles is substantially the same as Formulation 29 or 30.
- the additional therapeutic agent can be any of the additional therapeutic agents described herein.
- Preferred additional therapeutic agents are LAB As (e.g., formoterol, salmeterol), short-acting beta agonists (e.g., albuterol), corticosteroids (e.g., fluticasone), LAMAs (e.g., tiotropium), antibiotics (e.g., levofloxacin), recombinant human deoxyribonuclease I (e.g., dornase alfa also known as DNAse), sodium channel blockers (e.g., amiloride), and combinations thereof.
- LAB As e.g., formoterol, salmeterol
- short-acting beta agonists e.g., albuterol
- corticosteroids e.g., fluticasone
- LAMAs e.g., tiotropium
- antibiotics e.g., levofloxacin
- recombinant human deoxyribonuclease I
- Particularly preferred additional therapeutic agents are short-acting beta agonists (e.g., albuterol), antibiotics (e.g., levofloxacin), recombinant human deoxyribonuclease I (e.g., dornase alfa, also known as DNAse), sodium channel blockers (e.g., amiloride), and combinations thereof.
- beta agonists e.g., albuterol
- antibiotics e.g., levofloxacin
- recombinant human deoxyribonuclease I e.g., dornase alfa, also known as DNAse
- sodium channel blockers e.g., amiloride
- dry powder formulations that contain an additional therapeutic agent
- all or a portion of the leucine component in Formulation 29 or 30 is replaced with one or more additional therapeutic agents.
- This approach is particularly advantageous for additional therapeutic agents that require a higher effective dose, e.g., are not highly potent, and produces dry particles that deliver the beneficial effects of calcium cation in the respiratory tract and of the beneficial effects of the additional therapeutic agent(s).
- the dry particles are based on Formulation 29 and contain about 0.01% to about 20%) (w/w) of one or more additional therapeutic agent, about 75% (w/w) calcium lactate, about 5% (w/w) sodium chloride and about 20%> (w/w) or less leucine.
- the dry particles are based on Formulation 30 and contain about 0.01%) to about 37.5%o (w/w) of one or more additional therapeutic agents, about 58.6%> (w/w) calcium lactate, about 3.9% (w/w) sodium chloride and about 37.5% (w/w) or less leucine.
- the additional therapeutic agent can be any of the additional therapeutic agents described herein.
- Preferred additional therapeutic agent are LABAs (e.g., formoterol, salmeterol), short-acting beta agonists (e.g., albuterol), corticosteroids (e.g., fluticasone), LAMAs (e.g., tiotropium), antibiotics (e.g., levofloxacin, tobramycin), recombinant human deoxyribonuclease I (e.g., dornase alfa), and combinations thereof.
- LABAs e.g., formoterol, salmeterol
- short-acting beta agonists e.g., albuterol
- corticosteroids e.g., fluticasone
- LAMAs e.g., tiotropium
- antibiotics e.g., levofloxacin, tobramycin
- recombinant human deoxyribonuclease I e.g., dornase al
- additional therapeutic agents are short-acting beta agonists (e.g., albuterol), antibiotics (e.g., levofloxacin), recombinant human deoxyribonuclease I (e.g., dornase alfa, also known as DNAse), sodium channel blockers (e.g., amiloride), and combinations thereof.
- beta agonists e.g., albuterol
- antibiotics e.g., levofloxacin
- recombinant human deoxyribonuclease I e.g., dornase alfa, also known as DNAse
- sodium channel blockers e.g., amiloride
- dry powders that contain additional therapeutic agents are disclosed herein as Formulations X-XX.
- the dry particles are preferably small and dispersible. These dry particles are also calcium dense.
- the dry particles contain a high concentration of calcium salt (i.e., about 40% or more (w/w)) and are considered calcium salt dense.
- the dry particles of the invention have a VMGD, when measured at a dispersion (i.e., regulator) pressure setting of 1 bar, of about 5 microns or less, as measured by laser diffraction using a Spraytec system (particle size analysis instrument, Malvern Instruments) or using a HELOS/RODOS system (laser diffraction system with dry dispensing unit, Sympatec GmbH).
- the respirable dry particles have a VMGD as measured by laser diffraction at the dispersion pressure setting of 1.0 bar using a HELOS/RODOS system of about 5 microns or less (e.g., about 0.1 ⁇ to about 5 um), about 4 ⁇ or less (e.g., about 0.1 ⁇ to about 4 ⁇ ), about 3 ⁇ or less (e.g., about 0.1 ⁇ to about 3 ⁇ ), about 1 ⁇ to about 5 ⁇ , about 1 ⁇ to about 4 ⁇ , about 1.5 ⁇ to about 3.5 ⁇ , about 2 ⁇ to about 5 ⁇ , about 2 ⁇ to about 4 ⁇ , or about 2 ⁇ to about 3 ⁇ .
- the size is about 1 ⁇ to about 3 ⁇ .
- the respirable dry particles of can be large and dispersible, and preferably calcium dense.
- the respirable dry particles can have a VMGD as measured by HELOS/RODOS at the dispersion pressure setting of 1.0 bar of up to about 30 ⁇ .
- the preferred respirable dry powders e.g., Formulations 29 and 30
- the preferred respirable dry powders have a Hausner Ratio that is greater than 1.5, and can be 1.6 or higher, 1.7 or higher, 1.8 or higher, 1.9 or higher, 2 or higher, 2.1 or higher, 2.2 or higher, 2.3 or higher, 2.4 or higher, 2.5 or higher, 2.6 or higher or 2.7 or higher, between 2.2 and 2.9, between 2.2 and 2.8, between 2.2 and 2.7, between 2.2 and 2.6, between 2.2 and 2.5, between 2.3 and 2.5, between 2.6 and 2.8, about 2.7, or about 2.4.
- the respirable dry powders of have a Hausner Ratio that is 1.4 or higher.
- the respirable dry powders and respirable dry particles can have a heat of solution that is not highly exothermic.
- the heat of solution is determined using the ionic liquid of a simulated lung fluid (e.g. as described in Moss, O.R. 1979. Simulants of lung interstitial fluid. Health Phys. 36, 447-448; or in Sun, G. 2001. Oxidative interactions of synthetic lung epithelial lining fluid with metal-containing particulate matter. Am J Physiol Lung Cell Mol Physiol. 281, L807-L815) at pH 7.4 and 37°C in an isothermal calorimeter.
- the respirable dry powders or respirable dry particles can have a heat of solution that is less exothermic than the heat of solution of calcium chloride dihydrate, e.g., have a heat of solution that is greater than about -10 kcal/mol, greater than about -9 kcal/mol, greater than about -8 kcal/mol, greater than about -7 kcal/mol, greater than about -6 kcal/mol, greater than about -5 kcal/mol, greater than about -4 kcal/mol, greater than about -3 kcal/mol, greater than about -2 kcal/mol, greater than about -1 kcal/mol, about -10 kcal/mol to about 10 kcal/mol, about -8 kcal/mol to about 8 kcal/mol, or about -6 kcal/mol to about 6 kcal/mol.
- the heat of solution is between about -7 kcal/mol to about 7 kcal/mol, between about -6 kcal/mol to about 6 kcal/mol, or between about -5 kcal/mol to about 5 kcal/mol.
- the preferred respirable dry particles are dispersible, and have 1 bar/4 bar and/or 0.5 bar/4 bar of about 1.5 or less (e.g., about 1.0 to about 1.5).
- the dry particles have 1 bar/4 bar and/or 0.5 bar/4 bar of about 1.0 to about 1.2, and/or about 1.0 to about 1.1.
- the preferred respirable dry particles (e.g., Formulations 29 and 30 or based thereon) have an MMAD of about 10 microns or less, such as an MMAD of about 0.5 micron to about 10 microns.
- the dry particles of the invention have an MMAD of about 7 microns or less (e.g.
- micron to about 7 microns preferably about 1 micron to about 7 microns, or about 2 microns to about 7 microns, or about 3 microns to about 7 microns, or about 4 microns to about 7 microns, about 5 microns to about 7 microns, about 1 micron to about 6 microns, about 1 micron to about 5 microns, about 2 microns to about 5 microns, about 2 microns to about 4 microns, or about 3 microns.
- the size is about 1 ⁇ to about 3 ⁇ .
- the preferred respirable dry powders have an FPF of less than about 5.6 microns (FPF ⁇ 5.6 ⁇ ) of the total dose of at least about 30%, preferably at least about 40%>, or between about 40%> and about 50%>, at least 50%>, or between about 50%> and about 60%>, or at least 60%), or between about 60%> and about 70%>, or at least about 70%>; and preferably have a FPF of less than about 3.4 microns (FPF ⁇ 3.4 ⁇ ) of the total dose of at least about 20%, preferably at least about 25%, or between about 20%> and about 30%>, or at least 30%>, or between 30%> and about 40%>, or at least 40%>, or between 40%> and about 50%>, or at least 50%.
- the preferred respirable dry powders and dry particles preferably have a tap density of about 0.5 g/cm 3 to about 1.2 g/cm 3 .
- the small and dispersible dry particles of Formulation 29 and Formulation 30 can have a tap density of about 0.6 g/cm 3 to about 1.0 g/cm 3 , about 0.7 g/cm 3 to about 1.0 g/cm 3 , or about 0.8 g/cm 3 to about 1.0 g/cm 3.
- powders and particles that have a tap density that is less than about 0.5 g/cc, or less than about 0.4 g/cc can be prepared.
- the respirable dry powders and dry particles can have a water or solvent content of less than about 25%>, less than about 20%>, or less than about 15%> by weight of the respirable dry powder or particle.
- the respirable dry particles of the invention can have a water or solvent content of less than about 15% by weight, less than about 13% by weight, less than about 11.5% by weight, less than about 10%> by weight, less than about 9% by weight, less than about 8% by weight, less than about 7% by weight, less than about 6%> by weight, less than about 5% by weight, less than about 4% by weight, less than about 3% by weight, less than about 2% by weight, less than about 1% by weight or be anhydrous.
- the respirable dry particles of the invention can have a water or solvent content of less than about 6% and greater than about 1%, less than about 5.5% and greater than about 1.5%, less than about 5%) and greater than about 2%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, or about 5%.
- the preferred respirable dry powders and dry particles e.g., Formulations 29 and 30 or based thereon
- the respirable dry particles contain at least 10% calcium by weight of the dry powder (wt calcium/wt dry powder), at least 11% calcium by weight of the dry powder, at least 12%o calcium by weight of the dry powder; at least 13% calcium by weight of the dry powder, at least 14% calcium by weight of the dry powder, between 10%> and 12% calcium by weight of the dry powder, between 12% and 14% calcium by weight of the dry powder, about 11%) or about 13% calcium by weight of the dry powder.
- the respirable dry powder and dry particles of Formulation 29 and Formulation 30 contain a high percentage of calcium salt in the composition, and are calcium salt dense.
- the respirable dry particles contain at least 40% calcium salt by weight of the dry powder (wt calcium salt/wt dry powder), at least 50% calcium salt by weight of the dry powder, at least 55% calcium salt by weight of the dry powder; at least 60% calcium salt by weight of the dry powder, at least 70%) calcium salt by weight of the dry powder, between 40% and 90% calcium salt by weight of the dry powder, between 50% and 85% calcium salt by weight of the dry powder, about 55%) or about 80% calcium salt by weight of the dry powder.
- wt calcium salt/wt dry powder at least 50% calcium salt by weight of the dry powder, at least 55% calcium salt by weight of the dry powder
- at least 60% calcium salt by weight of the dry powder, at least 70% calcium salt by weight of the dry powder between 40% and 90% calcium salt by weight of the dry powder, between 50% and 85% calcium salt by weight of the dry powder, about 55%) or about 80% calcium salt by weight of the dry powder.
- the preferred respirable dry powders and dry particles contain a low percentage of sodium in the composition.
- the respirable dry particles contain less than 4% sodium by weight of the dry powder (wt sodium/wt dry powder), preferably 3% or less sodium by weight of the dry powder, or 2% or less sodium by weight of the dry powder.
- the respirable dry particles contain less than 6% sodium salt by weight of the dry powder, or about 5% or less sodium salt by weight of the dry powder.
- the respirable dry particles of Formulations 29 and 30 are characterized by the crystalline and amorphous content of the particles.
- the respirable dry particles can comprise a mixture of amorphous and crystalline content.
- calcium lactate can be substantially in the amorphous phase while sodium chloride or leucine can be substantially in the crystalline phase.
- the crystalline phase e.g., crystalline sodium chloride and/or crystalline leucine
- the amorphous phase e.g., amorphous calcium salt
- the preferred highly dispersible dry powders can be administered with low inhalation energy.
- R is the inhaler resistance in kPa /LPM
- Q is the steady flow rate in L/min
- V is the inhaled air volume in L.
- the preferred respirable dry powders and dry particles are characterized by a high emitted dose (e.g., CEPM of at least 75%, at least 80%), at least 85%, at least 90%>, at least 95%>) from a dry powder inhaler when a total inhalation energy of less than about 2 Joules or less than aboutl Joule, or less than about 0.8 Joule, or less than about 0.5 Joule, or less than about 0.3 Joule is applied to the dry powder inhaler.
- a high emitted dose e.g., CEPM of at least 75%, at least 80%
- at least 85%, at least 90%>, at least 95%> from a dry powder inhaler when a total inhalation energy of less than about 2 Joules or less than aboutl Joule, or less than about 0.8 Joule, or less than about 0.5 Joule, or less than about 0.3 Joule is applied to the dry powder inhaler.
- an emitted dose of at least 75%, at least 80%, at least 85%, at least 90%, at least 95% CEPM of Formulation 29 or Formulation 30 contained in a unit dose container, containing about 50 mg or about 40 mg of the appropriate formulation, in a dry powder inhaler can be achieved when a total inhalation energy of less than about 1 Joule (e.g., less than about 0.8 Joule, less than about 0.5 Joule, less than about 0.3 Joule) is applied to the dry powder inhaler.
- a total inhalation energy of less than about 1 Joule (e.g., less than about 0.8 Joule, less than about 0.5 Joule, less than about 0.3 Joule) is applied to the dry powder inhaler.
- An emitted dose of at least about 70% CEPM of respirable dry powder contained in a unit dose container, containing about 50 mg or about 40 mg of the respirable dry powder, in a dry powder inhaler can be achieved when a total inhalation energy of less than about 0.28 Joule is applied to the dry powder inhaler.
- the dry powder inhaler is a passive dry powder inhaler.
- the dry powder can fill the unit dose container, or the unit dose container can be at least 40% full, at least 50% full, at least 60% full, at least 70% full, at least 80% full, or at least 90% full.
- the unit dose container can be a capsule (e.g.
- the unit dose container can be a blister.
- the blister can be packaged as a single blister, or as part of a set of blisters, for example, 7 blisters, 14 blisters, 28 blisters, or 30 blisters.
- a 50 mg dose of Formulation 29 or Formulation 30 was found to require only 0.28 Joules to empty more than 70% of the fill weight in a single inhalation. All the adult patient populations listed above were calculated to be able to achieve greater than 2 Joules, 7 times more than the inhalational energy required.
- An advantage of the invention is that the preferred dry powders disperse well across a wide range of flow rates and are relatively flow rate independent, hence providing a relatively equal dosing across a variety of inspiratory flow rates.
- the preferred dry particles and powders enable the use of a simple, passive DPI for a wide patient population.
- respirable dry powder containing respirable dry particles of Formulation 29, that comprise i) about 20% (w/w) leucine, ii) about 75% (w/w) calcium lactate, and iii) about 5% (w/w) sodium chloride is used in the methods of the invention.
- the respirable dry powder or dry particles of Formulation 29 can be characterized by:
- VMGD at 1 bar as measured using a HELOS/RODOS system between 1 microns and 3 microns, preferably between 1.5 microns and 2.5 microns or between 2 microns and 3 microns;
- the respirable dry powder or dry particles of Formulation 29 can be further characterized by a water content of less then 25% by weight, preferably less than 15% or less than 10%) by weight, or less than 5% by weight, and by the presence of a mixture of amorphous and crystalline content, with calcium lactate substantially in the amorphous phase and sodium chloride and/or leucine substantially in the crystalline phase.
- the calcium lactate and sodium chloride are substantially in the amorphous phase and the leucine is in either the crystalline and/or amorphous phase.
- the respirable dry powder or dry particles of Formulation 29 can be further characterized by an emitted dose of at least about 80% of Formulation 29 contained in a unit dose container that contains 40 mg or more, or 50 mg or more, of Formulation 29, in a dry powder inhaler, when a total inhalation energy of less than about 0.5 Joule is applied to the dry powder inhaler; by an emitted dose of at least about 90% of Formulation 29 contained in a unit dose container that contains 40 mg or more, or 50 mg or more, of Formulation 29, in a dry powder inhaler, when a total inhalation energy of less than about 0.5 Joule is applied to the dry powder inhaler; or by an emitted dose of at least about 95% of Formulation 29 contained in a unit dose container containing 40 mg or more, or 50 mg or more of Formulation 29, in a dry powder inhaler, when a total inhalation energy of less than about 1 Joule is applied to the dry powder inhaler.
- respirable dry powder containing respirable dry particles of Formulation 29, that comprise i) about 20%> (w/w) leucine, ii) about 75% (w/w) calcium lactate, and iii) about 5% (w/w) sodium chloride is used in the methods of the invention.
- the respirable dry powder or dry particles can be characterized by:
- VMGD at 1 bar as measured using a HELOS/RODOS system between 1 microns and 3 microns, preferably between 1.5 microns and 2.5 microns or between 2 microns and 3 microns;
- respirable dry powder containing respirable dry particles of Formulation 30, that comprise i) about 37.5% (w/w) leucine, ii) about 58.6%> (w/w) calcium lactate, and iii) about 3.9% (w/w) sodium chloride is used in the methods of the invention.
- the respirable dry powder or dry particles of Formulation 30 can be characterized by:
- VMGD at 1 bar as measured using a HELOS/RODOS system between 1.5 microns and 3 microns, preferably between 2 microns and 3 microns;
- Hausner Ratio of 1.9 or higher, preferably between 2.0 and 3.0, and more preferably between 2.2 and 2.6;
- tap density of about 0.5 g/cm 3 to about 1.0 g/cm 3 preferably between about 0.6 g/cm 3 and about 1.0 g/cm 3 , or about 0.7 g/cm 3 and about 1.0 g/cm 3 .
- the respirable dry powder or dry particles of Formulation 30 can be further characterized by a water content of less then 25% by weight, preferably less than 15% or less than 10%) by weight, or less than 5% by weight, or less than 2% by weight, and by the presence of a mixture of amorphous and crystalline content, with calcium lactate substantially in the amorphous phase and sodium chloride and/or leucine substantially in the crystalline phase.
- the calcium lactate and sodium chloride are substantially in the amorphous phase and the leucine is in either the crystalline and/or amorphous phase.
- the respirable dry powder or dry particles of Formulation 30 can be further characterized by an emitted dose of at least about 70% of Formulation 30 contained in a unit dose container that contains 50 mg or more of Formulation 30, in a dry powder inhaler is achieved when a total inhalation energy of less than about 0.5 Joule is applied to the dry powder inhaler; or by an emitted dose of at least about 80% of Formulation 30 contained in a unit dose containing 50 mg or more of Formulation 30, in a dry powder inhaler is achieved when a total inhalation energy of less than about 1 Joule is applied to the dry powder inhaler.
- respirable dry particles and dry powders described herein are suitable for inhalation therapies.
- the respirable dry particles may be fabricated with the appropriate surface roughness, diameter and tap density for localized delivery to selected regions of the respiratory system such as the deep lung or upper or central airways.
- saline or calcium aerosols were topically delivered to the surface of a mucus mimetic (locus bean gum) followed by simulating a cough through the system and collecting the particles with an optical particle counter (CI-500B Climet Instruments, Redlands, CA) .
- mucus mimetic was mixed with Klebsiella pneumoniae and was added to the model trachea of the cough system. After exposure of the mimetic to 0.12M CaCl 2 in 0.90% sodium chloride or leaving the mimetic untreated, a cough was simulated and the particles were collected in liquid broth. Bacteria (particles) collected in the broth were diluted and plated on agar plates to enumerate the number of bacteria in each condition. Exposure of the mimetic to 0.12M CaCl 2 in 0.90% sodium chloride before cough simulation suppressed the number of particles formed by 75% compared to the untreated control (FIG. 1C).
- mice Specific pathogen-free female C57BL/6 mice (6-7 weeks, 16-22g) were used in these studies. Mice were given access to food and water ad libitum. For infections, S.
- Salt Formulation Aerosol Delivery Systems [00175] A whole-body exposure system using a high output nebulizer was utilized to deliver salt aerosols to a pie-chamber exposure system. Each pie chamber exposure chamber was modified such that a single tube delivered aerosol to a central manifold and ultimately to one of 11 mouse holding chambers via 4 inlet ports in each chamber. The total flow through the system was 11.7 L/min and animals were exposed to cationic aerosols for 15 minutes.
- Particle sizing of the aerosol generated by the high output nebulizer was performed using an inhaler adaptor set-up on a Sympatec Helos particle size analyzer outfitted with an R3 lens (0.5 to 175 ⁇ size range).
- the nebulizer was filled with 45mL isotonic saline (JT Baker, PhiUipsburg, NJ) and the outlet port of the tubing connected to the nebulizer was positioned ⁇ lcm from the inhaler adaptor. Each test measurement was taken for 5 seconds (C opt 16.5-29.31%) and the volume median diameter (MMD; x 50 ) and the geometric standard deviation were recorded for each measurement.
- Nebulizer output rates were determined by measuring the mass deposition onto collection filters. Filters were weighed immediately before collection and immediately after a 30 second collection period. Three test runs were performed using a fresh solution of isotonic saline for each measurement.
- E c Actual aerosol concentration delivered to the animals (mg/L air)
- RMV Respiratory Minute Volume (L/min.) according to the method of Bide et al.:
- RMV ( /mi .) 0.499 x BW (kg) 0'809 (estimated average over exposure period)
- T Time, duration of daily exposure (min.)
- BW Mean body weight (kg).
- mice were randomly assigned to different study groups on the day of the infections. Different aerosol exposure times relative to the time of infection were utilized to test the effect of aerosols in both prophylaxis and treatment regimens. For each exposure, mice were loaded into a customized whole-body pie chamber system in which aerosols were delivered to a central manifold and subsequently to each individual animal. Aerosol exposures consisted of a 15 minute exposure of 0.12M calcium chloride in 0.90% sodium chloride, which delivered an estimated dose of 6.4mg/kg/day of CaCl 2 . After 24 hours of infection, animals were euthanized by isoflurane inhalation and the lungs were surgically removed and placed in sterile water.
- CFU Colony forming units
- FIG. 2A A S. pneumoniae mouse model was employed to evaluate the treatment effect of salt on a bacterial infection.
- treatment 2.3 mg Ca/kg deposited dose
- Prophylactic treatment of bacterial pneumonia is driven by calcium chloride specifically and not divalent cations in general
- Bacteria were prepared by growing cultures on tryptic soy agar (TSA) blood plates overnight at 37°C plus 5%C0 2 . Single colonies were resuspended to an OD 6 oo ⁇ 0.3 in sterile PBS and subsequently diluted 1 :4 in sterile PBS [ ⁇ 2xl0 7 Colony forming units (CFU)/mL]. Mice were infected with 50 ⁇ of bacterial suspension ( ⁇ lxl0 6 CFU) by intratracheal instillation while under anesthesia.
- TSA tryptic soy agar
- C57BL6 mice were exposed to aerosolized liquid formulations in a whole-body exposure system using either a high output nebulizer or Pari LC Sprint nebulizers connected to a pie chamber cage that individually holds up to 11 animals. Treatments were performed 2 hours before infection with Serotype 3 Streptococcus pneumoniae. Unless otherwise stated, exposure times were 3 minutes in duration. Twenty-four hours after infection mice were euthanized by pentobarbital injection and lungs were collected and homogenized in sterile PBS. Lung homogenate samples were serially diluted in sterile PBS and plated on TSA blood agar plates. CFU were enumerated the following day.
- Calcium sodium formulations (Ca 2+ :Na + at 8:1 molar ratio) reduced bacterial burden in a dose responsive manner
- Figure 4A showed that that calcium:sodium formulations at an 8: 1 ratio of calcium to sodium reduced the severity of bacterial infections at doses of less than 1.58 mg Ca 2+ /kg.
- the IX formulation (Formulation 10, -0.72 mg Ca 2+ /kg) was the most highly effective.
- the study whose results were presented in Figure 4A tested a dose time of 3 minutes.
- mice C57BL6 were exposed to nebulized solutions of Ca:Na Formulation 10 (IX tonicity; 8: 1 molar ratio of Ca 2+ :Na + , delivered dose ⁇ 0.72mg Ca/kg), ampicillin in saline (96.75mg/mL in 0.9% NaCl, delivered dose ⁇ 3mg/kg), or ampicillin (96.75mg/mL) dissolved in the IX (Formulation 10) using whole body exposure chambers. Mice were exposed to each formulation 2h before infection with S. pneumonia. Both the IX Ca:Na formulation and the ampicillin alone reduced bacterial burden in the lungs of infected mice to the saline control (p ⁇ 0.001 Mann- Whitney U test).
- the IX formulation reduced bacterial titers approximately 4.5 -fold and the ampicillin reduced titers 33 -fold.
- the combination of the two therapies resulted in an even greater reduction in bacterial titers (333- fold) than either single treatment showing a therapeutic benefit to delivering inhaled antibiotics in the calcium formulations described herein. (FIG. 4C)
- volume median diameter (x50 or Dv50), which may also be referred to as volume median geometric diameter (VMGD)
- VMGD volume median geometric diameter
- the equipment consisted of a HELOS diffractometer and a RODOS dry powder disperser (Sympatec, Inc., Princeton, NJ).
- the RODOS disperser applies a shear force to a sample of particles, controlled by the regulator pressure (typically set at 1.0 bar with maximum orifice ring pressure) of the incoming compressed dry air.
- the pressure settings may be varied to vary the amount of energy used to disperse the powder.
- the dispersion energy may be modulated by changing the regulator pressure from 0.2 bar to 4.0 bar.
- Powder sample is dispensed from a microspatula into the RODOS funnel.
- the dispersed particles travel through a laser beam where the resulting diffracted light pattern produced is collected, typically using an Rl lens, by a series of detectors.
- the ensemble diffraction pattern is then translated into a volume- based particle size distribution using the Fraunhofer diffraction model, on the basis that smaller particles diffract light at larger angles. Using this method, geometric standard deviation (GSD) for the volume diameter was also determined.
- GSD geometric standard deviation
- volume median diameter can also be measured using a method where the powder is emitted from a dry powder inhaler device.
- the equipment consisted of a Spraytec laser diffraction particle size system (Malvern, Worcestershire, UK), "Spraytec”. Powder formulations were filled into size 3 HPMC capsules (Capsugel V-Caps) by hand with the fill weight measured gravimetrically using an analytical balance (Mettler Tolerdo XS205).
- a capsule based passive dry powder inhalers (RS-01 Model 7, High resistance Plastiape S.p.A.) was used which had specific resistance of 0.036 kPa 2 LPM _1 .
- Flow rate and inhaled volume were set using a timer controlled solenoid valve with flow control valve (TPK2000, Copley Scientific). Capsules were placed in the dry powder inhaler, punctured and the inhaler sealed to the inlet of the laser diffraction particle sizer. The steady air flow rate through the system was initiated using the TPK2000 and the particle size distribution was measured via the Spraytec at 1kHz for the durations at least 2 seconds and up to the total inhalation duration. Particle size distribution parameters calculated included the volume median diameter (Dv50) and the geometric standard deviation (GSD) and the fine particle fraction (FPF) of particles less than 5 micrometers in diameter.
- Dv50 volume median diameter
- GSD geometric standard deviation
- FPF fine particle fraction
- the Spraytec can be used in its "open bench configuration".
- capsules were placed in the dry powder inhaler, punctured and the inhaler sealed inside a cylinder.
- the cylinder was connected to a positive pressure air source with steady air flow through the system again measured with a mass flow meter and its duration controlled with a timer controlled solenoid valve.
- the exit of the dry powder inhaler was exposed to room pressure and the resulting aerosol jet passed through the laser of the diffraction particle sizer (Spraytec) in its open bench configuration before being captured by a vacuum extractor.
- the steady air flow rate through the system was initiated using the solenoid valve and the particle size distribution was measured via the Spraytec at 1kHz for the duration of the single inhalation maneuver with a minimum of 2 seconds, as in the closed bench configuration.
- the spraytec When data are reported in the examples as being measured by the Spraytec, they are from the open bench configuration unless otherwise noted.
- a short stack cascade impactor also referred to as a collapsed cascade impactor, is also utilized to allow for reduced labor time to evaluate two aerodynamic particle size cut-points. With this collapsed cascade impactor, stages are eliminated except those required to establish fine and coarse particle fractions.
- the impaction techniques utilized allowed for the collection of two or eight separate powder fractions.
- the capsules HPMC, Size 3; Shionogi Qualicaps, Madrid, Spain or Capsugel Vcaps, Peapack, NJ
- DPI breath-activated dry powder inhaler
- RS-01 DPI High resistance RS-01 DPI
- the calibrated cut-off diameters for the eight stages are 8.6, 6.5, 4.4, 3.3, 2.0, 1.1, 0.5 and 0.3 microns and for the two stages used with the short stack cascade impactor, the cut-off diameters are 5.6 microns and 3.4 microns.
- the fractions were collected by placing filters in the apparatus and determining the amount of powder that impinged on them by gravimetric measurements or chemical measurements on an HPLC, as labeled in the tables.
- the fine particle fraction of the total dose of powder (FPF TD ) less than or equal to an effective cut-off aerodynamic diameter was calculated by dividing the powder mass recovered from the desired stages of the impactor by the total particle mass in the capsule.
- Results are reported as the fine particle fraction of less than 5.6 microns (FPF TD ⁇ 5.6 microns) and the fine particle fraction of less than 3.4 microns (FPF TD ⁇ 3.4 microns).
- the fine particle fraction can alternatively be calculated relative to the recovered or emitted dose of powder by dividing the powder mass recovered from the desired stages of the impactor by the total powder mass recovered.
- Aerodynamic Diameter Mass median aerodynamic diameter (MMAD) was determined using the information obtained by the Andersen Cascade Impactor. The cumulative mass under the stage cut-off diameter is calculated for each stage and normalized by the recovered dose of powder. The MMAD of the powder is then calculated by linear interpolation of the stage cut-off diameters that bracket the 50th percentile.
- MMAD Mass median aerodynamic diameter
- Fine Particle Dose The fine particle dose was determined using the information obtained by the ACL The cumulative mass deposited on the final collection filter, and stages 6, 5, 4, 3, and 2 for a single dose of powder actuated into the ACI is equal to the fine particle dose less than 4.4 microns ( ⁇ 4.4 ⁇ ).
- Emitted Geometric or Volume Diameter The volume median diameter (Dv50) of the powder after it emitted from a dry powder inhaler, which may also be referred to as volume median geometric diameter (VMGD), was determined using a laser diffraction technique via the Spraytec diffractometer (Malvern, Inc.). Powder was filled into size 3 capsules (V-Caps, Capsugel) and placed in a capsule based dry powder inhaler (RS01 Model 7 High resistance, Plastiape, Italy), or DPI, which was connected airtightly to the inhaler adapter of the Spraytec.
- Dv50 volume median diameter of the powder after it emitted from a dry powder inhaler
- VMGD volume median geometric diameter
- a steady airflow rate was drawn through the DPI typically at 60 L/min for a set duration, typically of 2 seconds controlled by a timer controlled solenoid (TPK2000, Copley, Scientific, UK). Alternatively, the airflow rate drawn through the DPI was sometimes run at 15 L/min, 20 L/min, or 30 L/min.
- the outlet aerosol then passed perpendicularly through the laser beam as an internal flow.
- the resulting geometric particle size distribution of the aerosol was calculated from the software based on the measured scatter pattern on the photodetectors with samples typically taken at 1000Hz for the duration of the inhalation. The Dv50, GSD, ⁇ 5.0 ⁇ measured were then averaged over the duration of the inhalation.
- Capsule Emitted Powder Mass A measure of the emission properties of the powders was determined by using the information obtained from the Andersen Cascade Impactor tests or emitted geometric diameter by Spraytec. The filled capsule weight was recorded at the beginning of the run and the final capsule weight was recorded after the completion of the run. The difference in weight represented the amount of powder emitted from the capsule (CEPM or capsule emitted powder mass). The CEPM was reported as a mass of powder or as a percent by dividing the amount of powder emitted from the capsule by the total initial particle mass in the capsule. While the standard CEPM was measured at 60 L/min, it was also measured at 15 L/min, 20 L/min, or 30 L/min.
- Tap Density was measured using a modified method requiring smaller powder quantities, following USP ⁇ 616> with the substitution of a 1.5 cc
- microcentrifuge tube Eppendorf AG, Hamburg, Germany
- a disposable serological polystyrene micropipette Grenier Bio-One, Monroe, NC
- polyethylene caps Kimble Chase, Vineland, NJ
- Instruments for measuring tap density include but are not limited to the Dual Platform Microprocessor Controlled Tap Density Tester (Vankel, Cary, NC) or a SOTAX Tap Density Tester model TD2 (Horsham, PA).
- Tap density is a standard, approximated measure of the envelope mass density.
- the envelope mass density of an isotropic particle is defined as the mass of the particle divided by the minimum spherical envelope volume within which it can be enclosed.
- Bulk Density was estimated prior to tap density measurement procedure by dividing the weight of the powder by the volume of the powder, as estimated using the volumetric measuring device.
- Hausner Ratio a dimensionless number that is correlated to the flowability of a powder, was calculated by dividing the tap density by the bulk density.
- the ratios used for formulations were based on the molecular weight of the anhydrous salts. For certain salts, hydrated forms are more readily available than the anhydrous form. This required an adjustment in the ratios originally calculated, using a multiplier to correlate the molecular weight of the anhydrous salt with the molecular weight of the hydrate. An example of this calculation is included below.
- the weight percent of calcium ion in calcium lactate and calcium lactate pentahydrate is listed in Table 4.
- Niro Spray Dryer Dry powders were produced by spray drying utilizing a Niro Mobile Minor spray dryer (GEA Process Engineering Inc., Columbia, MD) with powder collection from a cyclone, a product filter or both. Atomization of the liquid feed was performed using a co-current two-fluid nozzle either from Niro (GEA Process Engineering Inc., Columbia, MD) or a Spraying Systems (Carol Stream, IL) two-fluid nozzle with gas cap 67147 and fluid cap 2850SS, although other two-fluid nozzle setups can also be utilized in a similar manner. In some embodiments, the two-fluid nozzle can be in an internal mixing setup or an external mixing setup.
- Niro Mobile Minor spray dryer GSA Process Engineering Inc., Columbia, MD
- Atomization of the liquid feed was performed using a co-current two-fluid nozzle either from Niro (GEA Process Engineering Inc., Columbia, MD) or a Spraying Systems (Carol Stream, IL) two-flui
- Additional atomization techniques include rotary atomization or a pressure nozzle.
- the liquid feed was fed using gear pumps (Cole -Parmer Instrument Company, Vernon Hills, IL) directly into the two-fluid nozzle or into a static mixer (Charles Ross & Son Company, Hauppauge, NY) immediately before introduction into the two-fluid nozzle.
- An additional liquid feed technique includes feeding from a pressurized vessel. Nitrogen or air may be used as the drying gas, provided that moisture in the air is at least partially removed before its use. Pressurized nitrogen or air can be used as the atomization gas feed to the two-fluid nozzle.
- the process gas inlet temperature can range from 70 °C to 300 °C and outlet temperature from 50 °C to 120 °C with a liquid feedstock rate of 10 mL/min to 100 mL/min.
- the gas supplying the two-fluid atomizer can vary depending on nozzle selection and for the Niro co-current two-fluid nozzle can range from 5 kg/hr to 50 kg/hr or for the Spraying Systems
- two-fluid nozzle with gas cap 67147 and fluid cap 2850SS can range from 30 g/min to 150 g/min.
- the atomizing gas rate can be set to achieve a certain gas to liquid mass ratio, which directly affects the droplet size created.
- the pressure inside the drying drum can range from +3 "WC to -6 "WC. Spray dried powders can be collected in a container at the outlet of the cyclone, onto a cartridge or baghouse filter, or from both a cyclone and a cartridge or baghouse filter.
- Inlet temperature of the process gas can range from 100 °C to 220 °C and outlet temperature from 60 °C to 120 °C with a liquid feedstock flowrate of 3 mL/min to 10 mL/min.
- the two-fluid atomizing gas ranges from 25 mm to 45 mm (300 LPH to 530 LPH) and the aspirator rate from 70% to 100% (28 m 3 /hr to 38 m 3 /hr).
- Table 5 provides feedstock formulations used in preparation of some dry powders described herein.
- dry powders exemplified herein are referred to by formulation number and have the chemical composition disclosed in Table 5. Dry powders produced using different solution preparations, equipment, or process parameters, but that have the same chemical composition, are referred to using differing capital letters. For example, Formulation I-A and I-B have the same chemical composition but were produced using different equipment and/or process parameters.
- Placebo formulations comprising either 100 wt% leucine (Placebo-A and Placebo- C) or 98 weight percent leucine with 2 weight percent sodium chloride (Placebo-B) were produced by spray drying.
- An aqueous phase was prepared for a batch process by dissolving leucine or leucine and sodium chloride in ultrapure water with constant agitation until the materials were completely dissolved in the water at room temperature. The solution was then spray dried using a Niro Mobile Minor spray dryer (GEA Process Engineering Inc.,
- the total liquid feedstock solids concentration was 15 g/L.
- Atomization of the liquid feed used a co-current two-fluid nozzle from Niro (GEA Process Engineering Inc., Columbia, MD) for Placebo-A and a Spraying Systems (Carol Stream, IL) two-fluid nozzle with gas cap 67147 and fluid cap 2850SS for Placebo-B and Placebo-C.
- the liquid feed was fed using gear pumps (Cole-Parmer Instrument Company, Vernon Hills, IL) into a static mixer (Charles Ross & Son Company, Hauppauge, NY) immediately before introduction into the two-fluid nozzle. Nitrogen was used as the drying gas.
- Process parameters are shown in Table 4, where the process gas inlet temperature, two-fluid atomization gas, process gas flowrate and liquid feedstock flowrate were controlled and the outlet temperature recorded.
- the pressure inside the drying chamber was controlled at -2 "WC. Spray dried powders were collected from a product collection filter.
- This example describes the preparation of dry powders using an aqueous feedstock, and the characteristics of the manufactured dry powder comprising of dry particles.
- the feedstock was prepared as a batch by dissolving leucine in ultrapure water, then sodium chloride, and finally calcium lactate pentahydrate. The solution was kept agitated throughout the process until the materials were completely dissolved in the water at room temperature. Details on a selection of the liquid feedstock preparation are shown in Table 7, where the total solids concentration is reported as the total of the dissolved anhydrous material weights. Formulations 29-A and 30- A were prepared with separate feedstocks utilizing a Niro spray dryer.
- Formulation 29- A and 30-A dry powders were produced by spray drying on the Niro Mobile Minor spray dryer (GEA Process Engineering Inc., Columbia, MD) with powder collection from a product filter.
- Atomization of the liquid feed used a Spraying Systems (Carol Stream, IL) two-fluid nozzle with gas cap 67147 and fluid cap 2850SS.
- the liquid feed was fed using gear pumps (Cole-Parmer Instrument Company, Vernon Hills, IL) directly into the two-fluid nozzle. Nitrogen was used as the drying gas. No humidification of the nitrogren drying gas was performed. Process parameters are shown in Table 8, where the process gas inlet temperature, two-fluid atomization gas, process gas flowrate and liquid feedstock flowrate were controlled and the outlet temperature recorded.
- the pressure inside the drying chamber was controlled at -2 "WC. Spray dried powders were collected from a product collection filter.
- Formulations 29-B and 30-B dry powders were produced by spray drying on the Buchi B-290 Mini Spray Dryer (BTJCHI Labortechnik AG, Flawil, Switzerland) with powder collection on a 60 mL glass vessel from a High Performance cyclone.
- the system used the Buchi B-296 dehumidifier and an external LG dehumidifier (model 49007903, LG
- Atomization of the liquid feed utilized a Buchi two-fluid nozzle with a 1.5 mm diameter.
- the two-fluid atomizing gas was set at 40 mm and the aspirator rate to 90%. Room air was used as the drying gas.
- inlet temperature of the process gas was 180 °C and outlet temperature at approximately 88 °C with a liquid feedstock flow rate of approximately 4.9 mL/min.
- the liquid feedstock solids concentration was 10 g/L in ultrapure water.
- inlet temperature of the process gas was from 96 °C to 105 °C to target an outlet temperature of approximately 97 °C to 100 °C with a liquid feedstock flowrate of approximately 4.9 mL/min.
- the liquid feedstock solids concentration for all of these runs was 5 g/L.
- Formulation 29 has a HELOS/RODOS dispersibility ratio at 1/4 bar and 0.5/4 bar dispersion energies of 1.05 each, while Formulation 30 has
- HELOS/RODOS dispersibility ratios at 1/4 bar and 0.5/4 bar dispersion energies of 1.07 and 1.18, respectively. Values that are close to 1.0, as these values are, are considered indicative that the powders are highly dispersible.
- EXAMPLE 4 Dispersibility: Emitted mass and particle size of Formulations 29 and 30 as a function of inhaled energy
- This example demonstrates the dispersibility of dry powder formulations comprising calcium lactate powders when delivered from a dry powder inhaler over a range of inhalation flow rate and volumes.
- Powder formulations were filled into size 3 HPMC capsules (Capsugel V-Caps) by hand with the fill weight measured gravimetrically using an analytical balance (Mettler Toledo XS205). Fill weights of 50 mg were filled for Formulations 29-A and 30-A.
- a capsule based passive dry powder inhaler (RS-01 Model 7, High Resistance, Plastiape S.p.A.) was used which had specific resistances of 0.036 kPa 1/2 LPM ⁇ ⁇ Flow rate and inhaled volume were set using a timer controlled solenoid valve with flow control valve with an inline mass flow meter (TSI model 3063).
- Capsules were placed in the dry powder inhaler, punctured and the inhaler sealed inside a cylinder, exposing the outlet of the DPI to the laser diffraction particle sizer (Spraytec, Malvern), also referred to herein as the Spraytec laser diffraction system (SLDS), in its open bench configuration.
- the steady air flow rate through the system was initiated using the solenoid valve and the particle size distribution was measured via the Spraytec at 1kHz for the duration of the single inhalation maneuver with a minimum of 2 seconds.
- Particle size distribution parameters calculated utilizing the laser diffraction particle sizer included the volume median diameter using the SLDS and called DV50S LD S SO as to avoid confusion with the HELOS/RODOS determined Dv50 and the geometric standard deviation, called GSDS LD S SO as to avoid confusion with the GSD of the HELOS/RODOS Dv50 data, and the fine particle fraction of particles less than 5 micrometers in diameter, using the SLDS, and called FPF SLD S ( ⁇ 5.0 ⁇ ) so as to avoid confusion with the FPF as determined on the Andersen Cascade Impactor.
- the dry powder inhaler was opened, the capsule removed and re-weighed to calculate the mass of powder that had been emitted from the capsule during the inhalation duration.
- 5 replicate capsules were measured and the results of DV50S LD S and FPFS LD S, and capsule emitted powder mass (CEPM) were averaged.
- R is the inhaler resistance in kPa /LPM
- Q is the steady flow rate in L/min
- V is the inhaled air volume in L.
- Emitted mass of Formulations 29-A and 30-A at a capsule fill weight of 50 mg using the high resistance RS-01 dry powder inhaler were determined. For each powder, a 2L inhalation was used at the high flow rate condition of 60 LPM, corresponding to the highest energy condition of 9.2 Joules. Three other flow rates, 30, 20 and 15 LPM, were tested using an inhalation volume of 1L. The entire mass of powder filled into the capsule emptied out of the capsule in a single inhalation for Formulation 29-A and 30-A at the highest energy condition tested.
- capsule dose emission dropped below 80% of the fill weight at 0.29 Joules.
- For Formulation 30- A capsule dose emission dropped below 80%> of the fill weight at 0.51 Joules.
- the particle size distributions of the emitted powder of Formulations 29-A and 30-A are listed in Table 10, characterized by the DV50S LD S and GSDS LD S as a function of the applied flow rate and inhalation energy. Consistent values of DV50S LD S at decreasing energy values indicate that the powder is well dispersed since additional energy does not result in additional deagglomeration of the emitted powder. The DV50S LD S values are consistent for all 4 Formulations with the mean DV50S LD S increasing by less than 2 micrometers from the highest inhalation energy condition (and hence most dispersed state) down to inhalation energies of 0.29 Joules.
- the mean DV50S LD S did not increase from baseline by 2 micrometers over the whole tested range with the maximum increase of 1.4 micrometers (from 2.1 to 3.5 micrometers) for a decrease of inhalation energy from 9.2 Joules to 0.29 Joules. In these ranges, the DV50S LD S is not significantly increased in size, which would be expected if the emitting powder contained a lot of agglomerates and was not well dispersed.
- the uniformity of the emitted dose of four powder formulations was measured by determining the mass of calcium which exited the dry powder inhaler (DPI) and was collected in a cylindrical sampling tube.
- the sampling tube was 120mm long and 35mm in diameter based on that specified in the United States Pharmacopeia ⁇ 601> and contained a 47 mm glass micro fiber filter (1820-047, Whatman) at the end to collect the aerosolized powder.
- a cylindrical cap, or mouthpiece adapter was connected to make an airtight seal to the DPI.
- Powder formulations were filled into size 3 HPMC capsules (V-Caps, Capsugel) by hand with the fill weight measured gravimetrically using an analytical balance (Mettler Toledo XS205). A fill weight of 50 mg was filled for
- Formulation 30-A and a fill weight of 40 mg was filled for Formulation 29-A.
- a reloadable, capsule based passive dry powder inhaler (RS-01 Model 7, High Resistance, Plastiape, Osnago, Italy) was used to disperse the powder into the sampling tube. Two capsules were used for each measurement, with two actuations of 2L of air at 60 LPM drawn through the dry powder inhaler (DPI) for each capsule. The flow rate and inhaled volume were set using a timer controlled solenoid valve with flow control valve (TPK2000 Copley Scientific). Ten replicate emitted dose measurements were performed for Formulations 29-A and 30- A.
- the inner surfaces of the sampling tube, mouthpiece adapter and 47mm glass microfiber filter were rinsed with 75 mL of water and the rinse solutions assayed by HPLC for calcium ion concentration.
- the measured emitted calcium mass was divided by the calcium present in the filled capsules (calculated from the measured fill weight of the individual capsules and the known calcium content of the powder formulation) to give the emitted dose as a percentage.
- the average emitted dose and standard deviation for each formulation is shown in Table 11.
- the nominal calcium content of the filled doses was 11 mg of calcium for both formulations with Formulation 30-A having 2 capsules per dose with 50 mg of powder in each capsule and 10.8% calcium (w/w) in the formulation, and Formulation 29-A having 2 capsules per dose with 40 mg of powder in each capsule and 13.8% calcium (w/w) in the formulation.
- Both powders were found to have repeatable emitted doses as illustrated by the low standard deviations.
- High emitted dose of powder formulations from a DPI is important for minimizing the amount of powder needed to load into a DPI, both for cost of goods concerns and for maximizing the number of doses that can be contained in a given inhaler.
- the average emitted dose for the 2 formulations tested was 93.8%> of the filled powder, which indicates that the powders are efficiently aerosolized and delivered out of the DPI with minimal residual powder being left in the DPI or capsule.
- V 0 The powder mass and initial volume (V 0 ) were recorded and the pipette was attached to the anvil and run according to the USP method for determining tap density.
- the pippette was tapped using Tap Count 1 (500 taps) and the resulting volume V a was recorded.
- Tap Count 2 was used (750 taps) resulting in the new volume V . If VM > 98% of V A , the test was complete, otherwise Tap Count 3 was used (1250 taps) iteratively until Vt, n > 98% of Vb n-1 .
- Bulk density was estimated prior to tap density measurement by dividing the weight of the powder by the volume of the powder, as estimated using the volumetric measuring device. Calculations were made to determine the powder bulk density (d B ), tap density (d T ), and Hausner Ratio (H), which is the tap density divided by the bulk density.
- Results for the density tests for Formulations 29 (29-A) and 30 (30- A) are shown in Table 12.
- the tap densities for all formulations are high (greater than 0.7 g/cc), especially for Formulation 29 (0.89 g/cc).
- the bulk densities are such that the Hausner ratio is quite high for Formulations 29 and 30.
- These Hausner Ratios are described in the art as being characteristic of powders with extremely poor flow properties (See, e.g., USP ⁇ 1174>).
- USP ⁇ 1174> notes that dry powders with a Hausner ratio greater than 1.35 are classified as poor flowing powders. Flow properties and dispersibility are both negatively affected by particle agglomeration or aggregation. It is therefore unexpected that powders with Hasuner Ratios of 1.4 to 3.2 would be highly dispersible and possess good aerosolization properties.
- the dose filled was two capsules of 50 mg powder fill weight which corresponded to 10.8mg of Ca 2+ filled into the capsules.
- the two capsules of 40mg of powder filled contained the same 10.8mg of Ca 2+ due to that formulation's higher Ca 2+ content.
- mDSC experiments were performed utilizing a DSCQ200 System from TA Instruments Inc. Approximately 10 mg of samples were placed inside hermetically sealed pans. The mDSC conditions utilized were: (i) equilibration at 0°C and modulation with a heating rate of 2°C/min, and (ii) amplitude of 0.32°C and period of 60s until 250°C. Glass transition temperatures were determined by the inflection point of the step change in the reversible heat flow versus temperature curve. Using this method, the T g of Formulation 29- C was determined to be approximately 107°C and Formulation 30-C approximately 91°C.
- Formulations 29-C and 30-C were analyzed for amorphous/crystalline content and polymorphic form using high resolution X-ray powder diffraction (XRPD).
- XRPD X-ray powder diffraction
- phase identification was performed to identify any crystalline phases observed in each XRPD pattern.
- XRPD patterns were collected using a PANalytical X'Pert Pro diffractometer (Almelo, The Netherlands).
- the specimen was analyzed using Cu radiation produced using an Optix long fine-focus source.
- An elliptically graded multilayer mirror was used to focus the Cu Ka X-rays of the source through the specimen and onto the detector.
- the specimen was sandwiched between 3 -micron thick films, analyzed in transmission geometry, and rotated to optimize orientation statistics.
- a beam- stop was used to minimize the background generated by air scattering.
- Soller slits were used for the incident and diffracted beams to minimize axial divergence.
- Diffraction patterns were collected using a scanning position- sensitive detector (X'Celerator) located 240 mm from the specimen. Scans were obtained over 3-60° with a step size of 0.017° and a step time of 70s. Peaks at approximately 6, 19, 24, 31 and 33° characteristic of leucine (leucine scan not shown) were observed in the
- SEM images were obtained of Formulation 29-B.
- SEM was performed using a FEI Quanta 200 Scanning Electron Microscope equipped with an Everhart Thornley (ET) detector. Images were collected and analyzed using xTm (v. 2.01) and XT Docu (v. 3.2) software. The magnification was verified using a NIST traceable standard.
- the sample was prepared for analysis by placing a small amount of specimen on a carbon adhesive tab supported on an aluminum mount. The sample was then sputter coated twice with Au/Pd using a Cresington 108auto Sputter Coater at approximately 20 mA and 0.13 mbar (Ar) for 75 seconds. The samples was observed under high vacuum using a beam voltage of 5 kV.
- the SEM image showed that Formulation 29-B is composed of partially collapsed spherical particles with sizes ranging from approximately 0.5 to 5 ⁇ .
- a p38 MAP kinase inhibitor ADS110836 was used as a reference agent (WO2009/098612 Example 1 1) and was administered by an intranasal route.
- RMV respiratory minute volume of the animal (0.21 LPM)
- T is the exposure time
- BW is the body weight of the animal in kg.
- the resulting estimated dose is then adjusted for the respirable fraction of the aerosol, which is determined based on the fine particle fraction (FPF; % mass less than 5.6 ⁇ ).
- Inflammatory cell counts in the BAL fluid of animals exposed to TS for 4 days were determined.
- TS exposed animals were exposed to Formulation 30-A or a control dry powder of 100% leucine.
- the leucine treated animals exposed to TS exhibited a 10-fold increase in total cell counts compared to air treated animals that were also administered the control powder. The magnitude of this increase demonstrates the degree of inflammation observed after 4-days of TS exposure.
- Additional groups of animals were exposed to Formulation 30-A.
- Formulation 30-A was give b.i.d. at two different doses (3 capsules of dry powder and 6 capsules of dry powder, where each capsule contained 150 mg of dry powder). The results are summarized in Table 18.
- the data show a dose responsive result for Formulation 30-A whereby doubling the dose from 3 capsules b.i.d. to 6 capsule b.i.d. causes an increased inhibition of total inflammatory cells, macrophages, epithelial cells, neutrophils, and lymphocytes.
- B. Formulation 29 reduces COPD-associated inflammation both prophylactically and therapeutically.
- mice C57BL6/J were exposed to TS by whole body exposure for up to 45 minutes per day.
- mice C57BL6/J were treated once daily with Formulation 29 (-1.6 mg Ca/kg) by whole body exposure 1 hour before TS exposure beginning on day 0 and continuing to day 11.
- mice were administered a p38 MAPK inhibitor (+ control; 100 ⁇ g/kg) intranasally once a day beginning on day 0.
- Control mice were treated with a dry powder comprised of 100% leucine. Data were analyzed by one-way ANOVA *p ⁇ 0.001.
- TS exposure significantly increased the number of macrophages, neutrophils and lymphocytes compared to air treated animals (FIG. 5A-C).
- Prophylactic or therapeutic dosing with Formulation 29 significantly reduced the number of all three cell types to statistically significant levels (FIG 5A-C).
- Formulation 29 when administered therapeutically (after the mice had already been exposed to TS for several days) was equally as effective at reducing macrophage, neutrophil and lymphocyte levels as the p38 MAPK inhibitor administered prophylactically from day 0.
- EXAMPLE 10 Dry powders reduce the expression of inflammatory chemokines/cytokines
- Control animals were exposed to a dry powder formulation of 100% leucine and a second control group was treated with leucine, but not exposed to TS.
- a p38 MAP kinase inhibitor ADS110836 was used as a reference agent (WO2009/098612 Example 11) and was administered by an intranasal route.
- BAL bronchoalveolar lavages
- BAL samples were assayed for a panel of 13 different cytokines and chemokines that have a role in the inflammation. Protein levels were assessed in a multiplex assay using Luminex technology and concentrations of each protein were determined from standard curves.
- KC and MIP2 represent two key neutrophil chemokines and perform a function analogous to IL-8 in humans. KC and MIP2 expression is upregulated by exposure to TS (see FIGs 6A-B, Leu Air versus Leu bars). Treatment with either Formulation IV-A or 30-A reduced the BAL levels of KC (FIG. 6A) and MIP2 (FIG. 6B) compared to leucine treated animals. The data were similar to the effects of these same formulations on neutrophil chemotaxis to the lung in the same animals and suggested that one mechanism by which the formulations reduce neutrophilic
- a mouse model of bacterial pneumonia was used to evaluate the efficacy of calcium lactate dry powder formulations in vivo.
- Bacteria ⁇ Streptococcus were prepared by growing cultures on tryptic soy agar (TSA) blood plates overnight at 37°C plus 5%C0 2 . Single colonies were re-suspended in sterile PBS to an optical density at 600 nm (OD 6 oo) of 0.3 in sterile PBS and subsequently diluted 1 :2 in sterile PBS [ ⁇ 4xl0 7 Colony forming units (CFU)/M1]. Mice were infected with 50 ⁇ of bacterial suspension ( ⁇ 2xl0 6 CFU) by intratracheal instillation while under anesthesia.
- C57BL6 mice were treated with either Placebo-C (100% Leucine) dry powder or Formulation 29-B for in a whole-body exposure system. Dry powder aerosol was generated using a capsule based system connected to a top-loading pie chamber cage that individually holds up to 11 animals. All dry powder treatments were delivered at 10 psi and 7 scfh (- 2.8 L/min). Treatments were performed either 2h before infection with Serotype 3 S. or 4 hours after infections. Twenty-four hours after infection mice were euthanized by pentobarbital injection and lungs were collected and homogenized in sterile PBS. Lung homogenate samples were serially diluted in sterile PBS and plated on TSA blood agar plates. Agar plates were incubated overnight at 37°C and CFU were enumerated the following day for quantification of bacterial burden in lungs.
- mice treated with Formulation 29-B using either dosing regimen had reduced bacterial counts in lung homogenate samples compared to animals treated with a control dry powder (Table 19). This suggests that such formulations may be beneficial as both a preventative treatment prior to pathogen exposure or alternatively as a therapeutic after the onset of infection.
- mice were then exposed to escalating doses of methacholine chloride (MCh) in 0.9% sodium chloride for inhalation via nebulization into the head chamber for 10 seconds.
- MCh methacholine chloride
- a liquid and a dry powder formulation were evaluated in an established sheep mucociliary clearance (MCC) model.
- MCC mucociliary clearance
- MCC was evaluated in four healthy sheep by measurement of the clearance of pulmonary Tc99m-labeled sulfur colloid aerosols that were delivered by inhalation.
- the radiolabeled sulfur colloid aerosol was delivered to each of the sheep via the same aerosol delivery system and MCC determined via the collection of serial images.
- a Pari LC jet nebulizer operating with a single sheep exposure system was used to deliver Formulation 13-A (which is 9.4% CaCl 2 (w/v), 0.62% NaCl (w/v) in water, at a concentration resulting in a tonicity factor of 8 times isotonic).
- the nebulizer was connected to a dosimeter system consisting of a solenoid valve and a source of compressed air (20 psi).
- the output of the nebulizer is connected to a T-piece, with one end attached to a respirator (Harvard Apparatus Inc., Holliston, MA).
- the system was activated for 1 second at the onset of the inspiratory cycle of the respirator, which was set at an inspiratory/expiratory ratio of 1 : 1 and a rate of 20 breaths/minute.
- a tidal volume of 300 ml was used to deliver the nebulized fomulation.
- the nebulizer was filled with 4mL of Formulation 13-A and run to dryness.
- a dry powder, Formulation 29, was delivered with a similar exposure system but with a rotating brush generator (RBG1000, Palas) used to generate the dry powder aerosol instead of the nebulizer.
- a 15 minute dose of the dry powder Formulation 29 was delivered with the aerosol continuously generated by the RBG.
- the dose delivered for both formulations was measured in- vitro with a breathing simulator system drawing the inspiratory flow through filter samples collected at the distal end of a tracheal tube.
- For the Formulation 29 dry powder 10 filter samples of 1.5 minutes each were assayed for deposited calcium by HPLC and the average rate of calcium deposition was determined, From this the dose delivered in 15 minutes to a 50kg sheep was calculated to be 0.5 mg Ca 2+ /kg.
- For the liquid Formulation 13-A 1.5 minute filter samples were again assayed for calcium content by HPLC and the dose delivered when running the 4mL solution to dryness was calculated for a 50kg sheep to be 0.5 mg Ca 2+ /kg. These measured doses correspond to the dose delivered from the distal end of the tracheal tube to the sheep during treatment.
- the sheep mucociliary clearance model is a well established model with vehicle clearance typically measuring approximately 5-10% at 60 minutes after delivery of the radioactive aerosol (see for example Coote et al, 2009, JEPT 329:769-774). It is known in the art that average clearance measurements greater than about 10% at 60 minutes post baseline indicate enhanced clearance in the model. Both the dry powder Formulation 29 and the liquid Formulation 13-A show enhanced mucociliary clearance in the sheep model, with average clearances ⁇ standard error at 60 minutes post baseline of 16.7% ⁇ 2.7% and 18.9% ⁇ 1.2% of baseline
- Feedstock solutions were prepared and used to manufacture dry powders comprised of neat, dry particles containing calcium lactate, sodium chloride, optionally leucine, and other therapeutic agents.
- Table 20 lists the components of the feedstock formulations used in preparation of the dry powders comprised of dry particles. Weight percentages are given on a dry basis.
- the liquid feedstock was batch mixed, the total solids concentration was 10 g/L, the amount of sodium chloride in 1 liter was 0.5 g, and the amount of calcium lactate pentahydrate in 1 liter was 10.6 g.
- Formulation X through XX dry powders were produced by spray drying on the Buchi B-290 Mini Spray Dryer (BTJCHI Labortechnik AG, Flawil, Switzerland) with powder collection on a 60 mL glass vessel from a High Performance cyclone.
- the system used the Buchi B-296 dehumidifier and an external LG dehumidifier (model 49007903, LG
- Powder physical and aerosol properties are summarized in Tables 23-26. Values with ⁇ indicates standard deviation of the value reported. Table 23 shows that all formulations had an FPF TD ⁇ 3.4 ⁇ greater than 18%. Formulations X, XI, XIV, XV, XVI, XVII, XVIII, and XIX each had an FPF TD ⁇ 3.4 ⁇ greater than 25%. Formulations X, XI, XV, and XVI each had FPF TD ⁇ 3.4 ⁇ greater than 30%. All formulations had an FPF TD ⁇ 5.6 ⁇ greater than 40%.
- Formulations X, XI, XIV, XV, XVI, XVII, XVIII and XIX had an FPF TD ⁇ 5.6 ⁇ greater than 50%.
- Formulation XV had an FPF TD ⁇ 5.6 ⁇ greater than 60%. All formulations had a tapped density greater than 0.45 g/cc.
- Formulations X, XII, XIII, XIV, XV, XVII, XVIII, XIX, and XX each had tapped densities greater than 0.5 g/cc.
- Formulations X, XIII, XIV, XVII, XVIII, XIX and XX each had tapped densities greater than 0.65 g/cc. All formulations had a Hausner Ratio greater than 1.8. Formulations XII, XIV,
- XVI, and XIX each had a Hausner Ratio equal to or greater than 2.4.
- Table 24 shows that all formulations had geometic diameters (Dv50) of less than 3.5 ⁇ at a dry powder inhaler flowrate of 60 LPM.
- Formulations X, XIII, XIV, XV, XVI, XVII, XVIII, XIX and XX had Dv50 of less than 2.5 ⁇ at 60 LPM. All formulations had a Dv50 of less than 6.0 ⁇ at 15 LPM.
- Formulations X, XIII, XIV, XV, XVII, XVIII, XIX and XX had a Dv50 of less than 4.6 ⁇ at 15 LPM.
- Formulations XIV, XV, XVII, XVIII, XIX and XX had a Dv50 of less than 4.0 ⁇ at 15 LPM.
- Table 25 shows that all formulations had a capsule emitted particle mass (CEPM) of greater than 94% at 60 LPM.
- Formulations X, XI, XII, XIV, XV, XVI, XVII, XVIII, XIX and XX each had a CEPM of greater than 97% at 60 LPM.
- Table 26 shows that all measured formulations had a Dv50 using the RODOS at its 1.0 bar setting of less than 2.5 ⁇ .
- Formulations X, XIII, XIV, XV, XVI, XVII, and XVIII each had a Dv50 of less than 2.2 ⁇ .
- Formulations X, XIII, XV, XVI, and XVII each had a Dv50 of less than 2.0 ⁇ . All measured formulations had a RODOS Ratio for 0.5/4 bar of less than 1.2. All measured formulations had a RODOS Ratio for 1/4 bar of less than 1.1.
- Formulation XI was evaluated in a mouse model of allergic asthma using ovalbumin (OVA) as an allergen.
- OVA ovalbumin
- mice were sensitized to OVA over a period of two weeks, on Day 0, 7, and 14, and subsequently challenged on days 27, 28, and 29, via a liquid aerosol, with OVA.
- This challenge induced lung inflammation and increased airway hyperreactivity in response to an airway challenge.
- the principle change in inflammation was an increase in the number of eosinophils in the lungs. Similar changes in lung inflammation and pulmonary function have been observed in humans with asthma.
- mice were sensitized and challenged to OVA, as per the sensitization protocol described above. Mice were treated with Placebo-B dry powder (98% leucine, 2% NaCl, w/w on a dry basis), Formulation 14-A (30% leucine, 65.4% NaCl, 4.0% fluticasone propionate and 0.13% salmeterol xinafoate, w/w on a dry basis), and Formulation XI (75.0% calcium lactate, 15.31%) leucine, 5.0% NaCl, 4.0%> fluticasone propionate and 0.58% salmeterol xinafoate, w/w on a dry basis).
- Placebo-B dry powder 98% leucine, 2% NaCl, w/w on a dry basis
- Formulation 14-A (30% leucine, 65.4% NaCl, 4.0% fluticasone propionate and 0.13% salmeterol xinafoate, w/w on a dry
- Treatments were made in a whole body exposure chamber using a capsule based dry powder inhaler system. Treatment was administered BID and took place on days 27, 28, 29, and 30. On the final day of the study (day 31), mice were euthanized and bronchoalveolar lavages (BAL) were performed. The total number of cells per BAL was determined. In addition, the percentage and total number of eosinophils, neutrophils, macrophages, and lymphocytes were determined by differential staining.
- Table 27 Formulation XI reduces eosinophilic and total cellular inflammation in a murine model of aller ic asthma
- mice sensitized and challenged with OVA exhibit increased airway hyperreactivity, which can be measured as changes in airway resistance following bronchoprovocation.
- Pulmonary function testing was conducted one hour following treatment on day 30. This involved measuring the specific airway resistance (sRaw) in the mice. Baseline sRaw measurements were taken for 5 minutes.
- mice subsequently underwent a methacholine (MCh) challenge for assessing pulmonary function with escalating concentrations of MCh delivered via nebulization in a head chamber using doses of MCh of 0 mg/ml, 50 mg/ml or 100 mg/ml.
- MCh methacholine
- mice were challenged to test their pulmonary function according to the methods described in Example 12. It was known from the literature, for example, (Schutz, N. (2004), "Prevention of bronchoconstriction in sensitized guinea pigs: efficacy of common prophylactic drugs", Respir Physiol Neurobiol 141(2): 167-178), and Ohta, S. et al.
- Non-calcium containing Formulations 14-A and 14-B were tested in order to contrast the efficacies of the calcium-containing Formulations XI and XIV, respectively. Results from pulmonary function testing are shown in FIG. 8 and FIG. 9 for Formulations XI and XIV, respectively. These data show that calcium-containing Formulation XIV matched the positive control, Formulation 14-B, and completely eliminates airway hyperreactivity in response to methacholine challenge in an OVA model of allergic asthma. Treatment with Formulation XI did not match the reduction in sRaw that Formulation 14-A achieved, however, the variability within the group treated with Formulation XI overlapped that of Formulation 14-A and the mean reduction was lower than that observed with Placebo-B.
- mice were exposed to whole body exposure with nebulized LPS, 1.12 mg/ml, for 30 minutes. Treatment with dry powder Formulations XI (75.0% calcium lactate, 15.31%
- mice with Formulation XI significantly reduced total cell counts and neutrophils in the BAL fluid when compared with animals exposed to Placebo-B and reduced inflammatory cells to a greater extent than the calcium- free Formulation 14-A.
- treatment of mice with Formulation XI significantly reduced lung inflammation in an LPS model of acute lung injury.
- Levofloxacin in a Pseudomonas aeruginosa mouse model [00277] A mouse model of bacterial infection was used to evaluate the efficacy of Formulation XVII in vivo. Neutropenia was induced by injection of cyclophosphamide (100 mg/Kg) on days -4 and -1. Bacteria (Pseudomonas aeruginosa) were grown overnight in 2 ml of Luria Bertani broth at 37C and approximately 5000 CFU were delivered per mouse via intranasal administration in 50 ⁇ of PBS.
- Co-formation of a calcium salt and a protein provides for delivery of the protein both locally in the lungs and systemically
- Formulation XVIII 75.0% calcium lactate, 17.5% leucine, 5.0% sodium chloride, 2.5% bovine immunoglobulin G (IgG), w/w on a dry basis
- IgG bovine immunoglobulin G
- mice were treated with Formulation XVIII using a whole body exposure chamber using a capsule based dry powder inhaler system. Animals were then treated with 2, 4 or 6 capsules of Formulation XVIII with another group of animals were treated with 6 capsules of Placebo-B control powder (98% leucine, 2% NaCl). The placebo controls were run to ensure that there was no cross reactivity with the bovine IgG assay and native mouse proteins in either the serum or the broncho-alveolar lavage (BAL). Immediately following DP treatment the animals were euthanized, underwent BAL and serum was collected. Lavage fluid and serum were then assayed for bovine IgG using a commercially available ELISA kit.
- Table 30 Calcium containing, inhaled dry powders can be utilized to deliver proteins to the lungs and systemically
- n 6 animals each for the 2, 4, and 6 capsule groups
- epithelial cell cultures are derived from CF-subjects and harbor a defined mutation in CFTR.
- human epithelial cell cultures are cultured on 12-well or 24-well Transwell plates under air- liquid interface conditions and treated topically with calcium dry powder formulations.
- the leucine control comprises of L-leucine and does not comprise of a calcium salt.
- Example 3 A The ability of calcium dry powder formulations to disperse or modulate the structure of established biofilms is assessed in a similar system to that described in Example 3 A.
- Biofilms are established on cultured epithelial cells and subsequently treated with calcium dry powder formulations. Treatments are made at multiple doses and at different time points after biofilm formation. Biofilm stability is assayed by fluorescence microscopy and by determining colony counts from wells at selected time points.
- the calcium dry powder formulations comprise of a calcium salt (calcium lactate), a sodium salt (sodium chloride), and leucine as an excipient.
- Wells treated with calcium dry powder formulations are compared to untreated wells and to leucine control treated wells.
- the leucine control comprises of L-leucine and does not comprise of a calcium salt.
- calcium dry powder formulations are made with D- leucine and compared to calcium dry powders formulations made with L-Leucine, as well as with a control comprising of L-leucine. In other experiments, one or both of these hypertonic calcium dry powder formulations are made with and without antibiotics. [00285] The entire teachings of all documents cited herein are hereby incorporated herein by reference.
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Also Published As
Publication number | Publication date |
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US8992983B2 (en) | 2015-03-31 |
US20150202227A1 (en) | 2015-07-23 |
EP2448571A1 (de) | 2012-05-09 |
US20130149345A1 (en) | 2013-06-13 |
EP2464346A1 (de) | 2012-06-20 |
EP2448571B1 (de) | 2013-06-12 |
US20150004233A1 (en) | 2015-01-01 |
WO2012030645A1 (en) | 2012-03-08 |
US20130164338A1 (en) | 2013-06-27 |
US8758824B2 (en) | 2014-06-24 |
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